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Paul L. Modrich

James B. Duke Distinguished Professor Emeritus of Biochemistry
Biochemistry
Box 3711 Med Ctr, Durham, NC 27710
156A Nanaline H Duke, Durham, NC 27708

Selected Publications


Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.

Journal Article Proc Natl Acad Sci U S A · February 18, 2020 MutL proteins are ubiquitous and play important roles in DNA metabolism. MutLγ (MLH1-MLH3 heterodimer) is a poorly understood member of the eukaryotic family of MutL proteins that has been implicated in triplet repeat expansion, but its action in this dele ... Full text Link to item Cite

The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutLα endonuclease.

Journal Article Proc Natl Acad Sci U S A · July 10, 2018 MutLα (MLH1-PMS2 heterodimer), which acts as a strand-directed endonuclease during the initiation of eukaryotic mismatch repair, has been postulated to function as a zinc-dependent enzyme [Kosinski J, Plotz G, Guarné A, Bujnicki JM, Friedhoff P (2008) J Mo ... Full text Link to item Cite

Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair.

Journal Article Proc Natl Acad Sci U S A · May 9, 2017 Eukaryotic MutLα (mammalian MLH1-PMS2 heterodimer; MLH1-PMS1 in yeast) functions in early steps of mismatch repair as a latent endonuclease that requires a mismatch, MutSα/β, and DNA-loaded proliferating cell nuclear antigen (PCNA) for activation. We show ... Full text Link to item Cite

Mechanisms in E. coli and Human Mismatch Repair (Nobel Lecture).

Journal Article Angew Chem Int Ed Engl · July 18, 2016 DNA molecules are not completely stable, they are subject to chemical or photochemical damage and errors that occur during DNA replication resulting in mismatched base pairs. Through mechanistic studies Paul Modrich showed how replication errors are correc ... Full text Link to item Cite

The C-terminal 20 Amino Acids of Drosophila Topoisomerase 2 Are Required for Binding to a BRCA1 C Terminus (BRCT) Domain-containing Protein, Mus101, and Fidelity of DNA Segregation.

Journal Article J Biol Chem · June 17, 2016 Eukaryotic topoisomerase 2 (Top2) and one of its interacting partners, topoisomerase IIβ binding protein 1 (TopBP1) are two proteins performing essential cellular functions. We mapped the interacting domains of these two proteins using co-immunoprecipitati ... Full text Link to item Cite

MutL traps MutS at a DNA mismatch.

Journal Article Proc Natl Acad Sci U S A · September 1, 2015 DNA mismatch repair (MMR) identifies and corrects errors made during replication. In all organisms except those expressing MutH, interactions between a DNA mismatch, MutS, MutL, and the replication processivity factor (β-clamp or PCNA) activate the latent ... Full text Link to item Cite

Hydrolytic function of Exo1 in mammalian mismatch repair.

Journal Article Nucleic Acids Res · June 2014 Genetic and biochemical studies have previously implicated exonuclease 1 (Exo1) in yeast and mammalian mismatch repair, with results suggesting that function of the protein in the reaction depends on both its hydrolytic activity and its ability to interact ... Full text Link to item Cite

Coupling of human DNA excision repair and the DNA damage checkpoint in a defined in vitro system.

Journal Article J Biol Chem · February 21, 2014 DNA repair and DNA damage checkpoints work in concert to help maintain genomic integrity. In vivo data suggest that these two global responses to DNA damage are coupled. It has been proposed that the canonical 30 nucleotide single-stranded DNA gap generate ... Full text Link to item Cite

Extrahelical (CAG)/(CTG) triplet repeat elements support proliferating cell nuclear antigen loading and MutLα endonuclease activation.

Journal Article Proc Natl Acad Sci U S A · July 23, 2013 MutLα endonuclease can be activated on covalently continuous DNA that contains a MutSα- or MutSβ-recognizable lesion and a helix perturbation that supports proliferating cell nuclear antigen (PCNA) loading by replication factor C, providing a potential mec ... Full text Link to item Cite

Christian Raetz: scientist and friend extraordinaire.

Journal Article Annu Rev Biochem · 2013 Chris Raetz passed away on August 16, 2011, still at the height of his productive years. His seminal contributions to biomedical research were in the genetics, biochemistry, and structural biology of phospholipid and lipid A biosynthesis in Escherichia col ... Full text Link to item Cite

PARP-1 enhances the mismatch-dependence of 5'-directed excision in human mismatch repair in vitro.

Journal Article DNA Repair (Amst) · November 10, 2011 End-directed mismatch-provoked excision has been reconstituted in several purified systems. While 3'-directed excision displays a mismatch dependence similar to that observed in nuclear extracts (≈20-fold), the mismatch dependence of 5'-directed excision i ... Full text Link to item Cite

Purification, crystallization and preliminary X-ray diffraction analysis of the human mismatch repair protein MutSβ.

Journal Article Acta Crystallogr Sect F Struct Biol Cryst Commun · August 1, 2011 MutSβ is a eukaryotic mismatch repair protein that preferentially targets extrahelical unpaired nucleotides and shares partial functional redundancy with MutSα (MSH2-MSH6). Although mismatch recognition by MutSα has been shown to involve a conserved Phe-X- ... Full text Link to item Cite

Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family.

Journal Article Cell · April 15, 2011 Human exonuclease 1 (hExo1) plays important roles in DNA repair and recombination processes that maintain genomic integrity. It is a member of the 5' structure-specific nuclease family of exonucleases and endonucleases that includes FEN-1, XPG, and GEN1. W ... Full text Link to item Cite

BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair.

Journal Article Genes Dev · February 15, 2011 Repair of dsDNA breaks requires processing to produce 3'-terminated ssDNA. We biochemically reconstituted DNA end resection using purified human proteins: Bloom helicase (BLM); DNA2 helicase/nuclease; Exonuclease 1 (EXO1); the complex comprising MRE11, RAD ... Full text Link to item Cite

PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair.

Journal Article Proc Natl Acad Sci U S A · September 14, 2010 MutLα (MLH1-PMS2) is a latent endonuclease that is activated in a mismatch-, MutSα-, proliferating cell nuclear antigen (PCNA)-, replication factor C (RFC)-, and ATP-dependent manner, with nuclease action directed to the heteroduplex strand that contains a ... Full text Link to item Cite

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance.

Journal Article Proc Natl Acad Sci U S A · July 27, 2010 The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2E702K knock-in mice. Pms2EK/EK mice displayed increa ... Full text Link to item Cite

Structure of the endonuclease domain of MutL: unlicensed to cut.

Journal Article Mol Cell · July 9, 2010 DNA mismatch repair corrects errors that have escaped polymerase proofreading, increasing replication fidelity 100- to 1000-fold in organisms ranging from bacteria to humans. The MutL protein plays a central role in mismatch repair by coordinating multiple ... Full text Link to item Cite

MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta.

Journal Article J Biol Chem · April 9, 2010 MutSbeta (MSH2-MSH3) mediates repair of insertion-deletion heterologies but also triggers triplet repeat expansions that cause neurological diseases. Like other DNA metabolic activities, MutSbeta interacts with proliferating cell nuclear antigen (PCNA) via ... Full text Link to item Cite

Interactions of human mismatch repair proteins MutSalpha and MutLalpha with proteins of the ATR-Chk1 pathway.

Journal Article J Biol Chem · February 19, 2010 At clinically relevant doses, chemotherapeutic S(N)1 DNA methylating agents induce an ATR-mediated checkpoint response in human cells that is dependent on functional MutSalpha and MutLalpha. Deficiency of either mismatch repair activity renders cells highl ... Full text Link to item Cite

Involvement of the beta clamp in methyl-directed mismatch repair in vitro.

Journal Article J Biol Chem · November 20, 2009 We have examined function of the bacterial beta replication clamp in the different steps of methyl-directed DNA mismatch repair. The mismatch-, MutS-, and MutL-dependent activation of MutH is unaffected by the presence or orientation of loaded beta clamp o ... Full text Link to item Cite

Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.

Journal Article Proc Natl Acad Sci U S A · February 18, 2020 MutL proteins are ubiquitous and play important roles in DNA metabolism. MutLγ (MLH1-MLH3 heterodimer) is a poorly understood member of the eukaryotic family of MutL proteins that has been implicated in triplet repeat expansion, but its action in this dele ... Full text Link to item Cite

The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutLα endonuclease.

Journal Article Proc Natl Acad Sci U S A · July 10, 2018 MutLα (MLH1-PMS2 heterodimer), which acts as a strand-directed endonuclease during the initiation of eukaryotic mismatch repair, has been postulated to function as a zinc-dependent enzyme [Kosinski J, Plotz G, Guarné A, Bujnicki JM, Friedhoff P (2008) J Mo ... Full text Link to item Cite

Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair.

Journal Article Proc Natl Acad Sci U S A · May 9, 2017 Eukaryotic MutLα (mammalian MLH1-PMS2 heterodimer; MLH1-PMS1 in yeast) functions in early steps of mismatch repair as a latent endonuclease that requires a mismatch, MutSα/β, and DNA-loaded proliferating cell nuclear antigen (PCNA) for activation. We show ... Full text Link to item Cite

Mechanisms in E. coli and Human Mismatch Repair (Nobel Lecture).

Journal Article Angew Chem Int Ed Engl · July 18, 2016 DNA molecules are not completely stable, they are subject to chemical or photochemical damage and errors that occur during DNA replication resulting in mismatched base pairs. Through mechanistic studies Paul Modrich showed how replication errors are correc ... Full text Link to item Cite

The C-terminal 20 Amino Acids of Drosophila Topoisomerase 2 Are Required for Binding to a BRCA1 C Terminus (BRCT) Domain-containing Protein, Mus101, and Fidelity of DNA Segregation.

Journal Article J Biol Chem · June 17, 2016 Eukaryotic topoisomerase 2 (Top2) and one of its interacting partners, topoisomerase IIβ binding protein 1 (TopBP1) are two proteins performing essential cellular functions. We mapped the interacting domains of these two proteins using co-immunoprecipitati ... Full text Link to item Cite

MutL traps MutS at a DNA mismatch.

Journal Article Proc Natl Acad Sci U S A · September 1, 2015 DNA mismatch repair (MMR) identifies and corrects errors made during replication. In all organisms except those expressing MutH, interactions between a DNA mismatch, MutS, MutL, and the replication processivity factor (β-clamp or PCNA) activate the latent ... Full text Link to item Cite

Hydrolytic function of Exo1 in mammalian mismatch repair.

Journal Article Nucleic Acids Res · June 2014 Genetic and biochemical studies have previously implicated exonuclease 1 (Exo1) in yeast and mammalian mismatch repair, with results suggesting that function of the protein in the reaction depends on both its hydrolytic activity and its ability to interact ... Full text Link to item Cite

Coupling of human DNA excision repair and the DNA damage checkpoint in a defined in vitro system.

Journal Article J Biol Chem · February 21, 2014 DNA repair and DNA damage checkpoints work in concert to help maintain genomic integrity. In vivo data suggest that these two global responses to DNA damage are coupled. It has been proposed that the canonical 30 nucleotide single-stranded DNA gap generate ... Full text Link to item Cite

Extrahelical (CAG)/(CTG) triplet repeat elements support proliferating cell nuclear antigen loading and MutLα endonuclease activation.

Journal Article Proc Natl Acad Sci U S A · July 23, 2013 MutLα endonuclease can be activated on covalently continuous DNA that contains a MutSα- or MutSβ-recognizable lesion and a helix perturbation that supports proliferating cell nuclear antigen (PCNA) loading by replication factor C, providing a potential mec ... Full text Link to item Cite

Christian Raetz: scientist and friend extraordinaire.

Journal Article Annu Rev Biochem · 2013 Chris Raetz passed away on August 16, 2011, still at the height of his productive years. His seminal contributions to biomedical research were in the genetics, biochemistry, and structural biology of phospholipid and lipid A biosynthesis in Escherichia col ... Full text Link to item Cite

PARP-1 enhances the mismatch-dependence of 5'-directed excision in human mismatch repair in vitro.

Journal Article DNA Repair (Amst) · November 10, 2011 End-directed mismatch-provoked excision has been reconstituted in several purified systems. While 3'-directed excision displays a mismatch dependence similar to that observed in nuclear extracts (≈20-fold), the mismatch dependence of 5'-directed excision i ... Full text Link to item Cite

Purification, crystallization and preliminary X-ray diffraction analysis of the human mismatch repair protein MutSβ.

Journal Article Acta Crystallogr Sect F Struct Biol Cryst Commun · August 1, 2011 MutSβ is a eukaryotic mismatch repair protein that preferentially targets extrahelical unpaired nucleotides and shares partial functional redundancy with MutSα (MSH2-MSH6). Although mismatch recognition by MutSα has been shown to involve a conserved Phe-X- ... Full text Link to item Cite

Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family.

Journal Article Cell · April 15, 2011 Human exonuclease 1 (hExo1) plays important roles in DNA repair and recombination processes that maintain genomic integrity. It is a member of the 5' structure-specific nuclease family of exonucleases and endonucleases that includes FEN-1, XPG, and GEN1. W ... Full text Link to item Cite

BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair.

Journal Article Genes Dev · February 15, 2011 Repair of dsDNA breaks requires processing to produce 3'-terminated ssDNA. We biochemically reconstituted DNA end resection using purified human proteins: Bloom helicase (BLM); DNA2 helicase/nuclease; Exonuclease 1 (EXO1); the complex comprising MRE11, RAD ... Full text Link to item Cite

PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair.

Journal Article Proc Natl Acad Sci U S A · September 14, 2010 MutLα (MLH1-PMS2) is a latent endonuclease that is activated in a mismatch-, MutSα-, proliferating cell nuclear antigen (PCNA)-, replication factor C (RFC)-, and ATP-dependent manner, with nuclease action directed to the heteroduplex strand that contains a ... Full text Link to item Cite

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance.

Journal Article Proc Natl Acad Sci U S A · July 27, 2010 The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2E702K knock-in mice. Pms2EK/EK mice displayed increa ... Full text Link to item Cite

Structure of the endonuclease domain of MutL: unlicensed to cut.

Journal Article Mol Cell · July 9, 2010 DNA mismatch repair corrects errors that have escaped polymerase proofreading, increasing replication fidelity 100- to 1000-fold in organisms ranging from bacteria to humans. The MutL protein plays a central role in mismatch repair by coordinating multiple ... Full text Link to item Cite

MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta.

Journal Article J Biol Chem · April 9, 2010 MutSbeta (MSH2-MSH3) mediates repair of insertion-deletion heterologies but also triggers triplet repeat expansions that cause neurological diseases. Like other DNA metabolic activities, MutSbeta interacts with proliferating cell nuclear antigen (PCNA) via ... Full text Link to item Cite

Interactions of human mismatch repair proteins MutSalpha and MutLalpha with proteins of the ATR-Chk1 pathway.

Journal Article J Biol Chem · February 19, 2010 At clinically relevant doses, chemotherapeutic S(N)1 DNA methylating agents induce an ATR-mediated checkpoint response in human cells that is dependent on functional MutSalpha and MutLalpha. Deficiency of either mismatch repair activity renders cells highl ... Full text Link to item Cite

Involvement of the beta clamp in methyl-directed mismatch repair in vitro.

Journal Article J Biol Chem · November 20, 2009 We have examined function of the bacterial beta replication clamp in the different steps of methyl-directed DNA mismatch repair. The mismatch-, MutS-, and MutL-dependent activation of MutH is unaffected by the presence or orientation of loaded beta clamp o ... Full text Link to item Cite

Functions of MutLalpha, replication protein A (RPA), and HMGB1 in 5'-directed mismatch repair.

Journal Article J Biol Chem · August 7, 2009 A purified system comprised of MutSalpha, MutLalpha, exonuclease 1 (Exo1), and replication protein A (RPA) (in the absence or presence of HMGB1) supports 5'-directed mismatch-provoked excision that terminates after mismatch removal. MutLalpha is not essent ... Full text Link to item Cite

Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks.

Journal Article Nucleic Acids Res · July 2009 DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, thus ICL-inducing agents such as psoralen, are clinically useful chemotherapeutics. Psoralen-modified triplex-forming oligonucleotides (TFOs) have been used to target ICLs ... Full text Link to item Cite

A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair.

Journal Article Proc Natl Acad Sci U S A · May 26, 2009 Mismatch repair contributes to genetic stability, and inactivation of the mammalian pathway leads to tumor development. Mismatch correction occurs by an excision-repair mechanism and has been shown to depend on the 5' to 3' hydrolytic activity exonuclease ... Full text Link to item Cite

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair.

Journal Article Proc Natl Acad Sci U S A · November 4, 2008 The error-free repair of double-stranded DNA breaks by homologous recombination requires processing of broken ends. These processed ends are substrates for assembly of DNA strand exchange proteins that mediate DNA strand invasion. Here, we establish that h ... Full text Link to item Cite

Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma.

Journal Article Clin Cancer Res · August 1, 2008 PURPOSE: A major mechanism of resistance to methylating agents, including temozolomide, is the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Preclinical data indicates that defective DNA mismatch repair (MMR) results in tolerance to temo ... Full text Link to item Cite

The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair.

Journal Article J Biol Chem · May 9, 2008 We have examined the interaction parameters, conformation, and functional significance of the human MutSalpha(.) proliferating cell nuclear antigen (PCNA) complex in mismatch repair. The two proteins associate with a 1:1 stoichiometry and a K(D) of 0.7 mic ... Full text Link to item Cite

Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.

Journal Article Mol Cell · January 18, 2008 MutL alpha, the heterodimeric eukaryotic MutL homolog, is required for DNA mismatch repair (MMR) in vivo. It has been suggested that conformational changes, modulated by adenine nucleotides, mediate the interactions of MutL alpha with other proteins in the ... Full text Link to item Cite

Saccharomyces cerevisiae MutLalpha is a mismatch repair endonuclease.

Journal Article J Biol Chem · December 21, 2007 MutL homologs are crucial for mismatch repair and genetic stability, but their function is not well understood. Human MutLalpha (MLH1-PMS2 heterodimer) harbors a latent endonuclease that is dependent on the integrity of a PMS2 DQHA(X)2E(X)4E motif (Kadyrov ... Full text Link to item Cite

Protein roadblocks and helix discontinuities are barriers to the initiation of mismatch repair.

Journal Article Proc Natl Acad Sci U S A · July 31, 2007 The hemimethylated d(GATC) sequence that directs Escherichia coli mismatch repair can reside on either side of a mismatch at a separation distance of 1,000 bp or more. Initiation of repair involves the mismatch-, MutS-, and MutL-dependent activation of Mut ... Full text Link to item Cite

Structure of the human MutSalpha DNA lesion recognition complex.

Journal Article Mol Cell · May 25, 2007 Mismatch repair (MMR) ensures the fidelity of DNA replication, initiates the cellular response to certain classes of DNA damage, and has been implicated in the generation of immune diversity. Each of these functions depends on MutSalpha (MSH2*MSH6 heterodi ... Full text Link to item Cite

Mechanisms in eukaryotic mismatch repair.

Journal Article J Biol Chem · October 13, 2006 Full text Link to item Cite

Mismatch repair-dependent iterative excision at irreparable O6-methylguanine lesions in human nuclear extracts.

Journal Article J Biol Chem · August 11, 2006 The response of mammalian cells to Sn1 DNA methylators depends on functional MutSalpha and MutLalpha. Cells deficient in either of these activities are resistant to the cytotoxic effects of this class of chemotherapeutic drug. Because killing by Sn1 methyl ... Full text Link to item Cite

Endonucleolytic function of MutLalpha in human mismatch repair.

Journal Article Cell · July 28, 2006 Half of hereditary nonpolyposis colon cancer kindreds harbor mutations that inactivate MutLalpha (MLH1*PMS2 heterodimer). MutLalpha is required for mismatch repair, but its function in this process is unclear. We show that human MutLalpha is a latent endon ... Full text Link to item Cite

The beta sliding clamp binds to multiple sites within MutL and MutS.

Journal Article J Biol Chem · May 19, 2006 The MutL and MutS proteins are the central components of the DNA repair machinery that corrects mismatches generated by DNA polymerases during synthesis. We find that MutL interacts directly with the beta sliding clamp, a ring-shaped dimeric protein that c ... Full text Link to item Cite

A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group.

Journal Article J Neurooncol · April 2006 The role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent s ... Full text Link to item Cite

Analysis of the excision step in human DNA mismatch repair.

Journal Article Methods Enzymol · 2006 The reaction responsible for replication error correction by mismatch repair proceeds via several steps: mismatch recognition, mismatch-provoked excision, repair DNA synthesis, and ligation. Key steps in this process are the recognition and subsequent exon ... Full text Link to item Cite

Human mismatch repair: reconstitution of a nick-directed bidirectional reaction.

Journal Article J Biol Chem · December 2, 2005 Bidirectional mismatch repair directed by a strand break located 3' or 5' to the mispair has been reconstituted using seven purified human activities: MutSalpha, MutLalpha, EXOI, replication protein A (RPA), proliferating cell nuclear antigen (PCNA), repli ... Full text Link to item Cite

Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft.

Journal Article Mol Cancer Ther · September 2005 Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of temozolomide, particularly in cells deficient in DNA ... Full text Link to item Cite

HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.

Journal Article Mol Cell · March 18, 2005 Featured Publication Hypoxia promotes genetic instability by undefined mechanisms. The transcription factor HIF-1alpha is crucial for the cellular response to hypoxia and is frequently overexpressed in human cancers, resulting in the activation of genes essential for cell surv ... Full text Link to item Cite

Methyl-directed repair of DNA base-pair mismatches in vitro. 1983.

Journal Article DNA Repair (Amst) · January 2, 2005 Featured Publication Full text Link to item Cite

Early thinking on the nature of mismatch repair

Journal Article DNA Repair · January 2, 2005 Replication error correction by mismatch repair relies on the strand-directed nature of the reaction. Ephrussi-Taylor and Gray attributed the marker-dependent recovery of pneumoccocal transformants to a mismatch-provoked repair reaction characterized by a ... Full text Cite

Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations.

Journal Article Mol Cancer Ther · September 2004 Featured Publication The chemotherapeutic activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) may be improved by the addition of O6-benzylguanine (O6-BG). The reaction of O6-BG with O6-alkylguanine-DNA alkyltransferase (AGT) prevents the repair of O6-chloroet ... Link to item Cite

Differential specificities and simultaneous occupancy of human MutSalpha nucleotide binding sites.

Journal Article J Biol Chem · July 2, 2004 Featured Publication We have examined the permissible nucleotide occupancy states of human MutSalpha. The MSH2.MSH6 heterodimer binds 1 mol of ADP and 1 mol of adenosine 5'-O-(thiotriphosphate) (ATPgammaS), with a K(d) for each nucleotide of about 1 microm. Anisotropy measurem ... Full text Link to item Cite

A defined human system that supports bidirectional mismatch-provoked excision.

Journal Article Mol Cell · July 2, 2004 Featured Publication Mismatch-provoked excision directed by a strand break located 3' or 5' to the mispair has been reconstituted using purified human proteins. While MutSalpha, EXOI, and RPA are sufficient to support hydrolysis directed by a 5' strand break, 3' directed excis ... Full text Link to item Cite

Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90.

Journal Article Chem Biol · June 2004 Featured Publication Agents that inhibit Hsp90 function hold significant promise in cancer therapy. Here we present PU24FCl, a representative of the first class of designed Hsp90 inhibitors. By specifically and potently inhibiting tumor Hsp90, PU24FCl exhibits wide-ranging ant ... Full text Link to item Cite

The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase.

Journal Article Oncogene · May 6, 2004 Featured Publication The human MSH2/6 complex is essential for mismatch recognition during the repair of replication errors. Although mismatch repair components have been implicated in DNA homologous recombination repair, the exact function of hMSH2/6 in this pathway is unclea ... Full text Link to item Cite

Hydrolytically deficient MutS E694A is defective in the MutL-dependent activation of MutH and in the mismatch-dependent assembly of the MutS.MutL.heteroduplex complex.

Journal Article J Biol Chem · December 5, 2003 Featured Publication The roles of ATP binding and hydrolysis by MutS in mismatch repair are poorly understood. MutS E694A, in which Glu-694 of the Walker B motif is substituted with alanine, is defective in hydrolysis of bound ATP and has been reported to support MutL-dependen ... Full text Link to item Cite

Mechanism of 5'-directed excision in human mismatch repair.

Journal Article Mol Cell · November 2003 Featured Publication We have developed a purified system that supports mismatch-dependent 5'-->3' excision. In the presence of RPA, ATP, and a mismatch, MutSalpha activates 5'-->3' excision by EXOI, and excision terminates after removal of the mispair. MutSalpha confers high p ... Full text Link to item Cite

Assembly and molecular activities of the MutS tetramer.

Journal Article J Biol Chem · September 5, 2003 Featured Publication Analytical equilibrium ultracentrifugation indicates that Escherichia coli MutS exists as an equilibrating mixture of dimers and tetramers. The association constant for the dimer-to-tetramer transition is 2.1 x 10(7) M-1, indicating that the protein would ... Full text Link to item Cite

Differential and simultaneous adenosine di- and triphosphate binding by MutS.

Journal Article J Biol Chem · May 16, 2003 Featured Publication The roles of ATP binding and hydrolysis in the function of MutS in mismatch repair are poorly understood. As one means of addressing this question, we have determined the affinities and number of adenosine di- and triphosphate binding sites within MutS. Ni ... Full text Link to item Cite

Mechanisms of resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea in human medulloblastoma and rhabdomyosarcoma.

Journal Article Mol Cancer Ther · July 2002 Featured Publication Medulloblastoma (D-341 MED) and rhabdomyosarcoma (TE-671) cell lines, which are resistant to either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of BCNU and O6-benzylguanine (O6-BG), were generated by serial escalation of BCNU. The activi ... Link to item Cite

Human exonuclease I is required for 5' and 3' mismatch repair.

Journal Article J Biol Chem · April 12, 2002 Featured Publication We have partially purified a human activity that restores mismatch-dependent, bi-directional excision to a human nuclear extract fraction depleted for one or more mismatch repair excision activities. Human EXOI co-purifies with the excision activity, and t ... Full text Link to item Cite

High rate of CAD gene amplification in human cells deficient in MLH1 or MSH6.

Journal Article Proc Natl Acad Sci U S A · November 20, 2001 MutS and MutL homologs have been implicated in multiple genetic stabilization pathways. The activities participate in the correction of DNA biosynthetic errors, are involved in cellular responses to certain types of DNA damage, and serve to ensure the fide ... Full text Link to item Cite

Distinct MutS DNA-binding modes that are differentially modulated by ATP binding and hydrolysis.

Journal Article J Biol Chem · September 7, 2001 The role of MutS ATPase in mismatch repair is controversial. To clarify further the function of this activity, we have examined adenine nucleotide effects on interactions of Escherichia coli MutS with homoduplex and heteroduplex DNAs. In contrast to previo ... Full text Link to item Cite

DNA chain length dependence of formation and dynamics of hMutSalpha.hMutLalpha.heteroduplex complexes.

Journal Article J Biol Chem · August 31, 2001 Formation of a ternary complex between human MutSalpha, MutLalpha, and heteroduplex DNA has been demonstrated by surface plasmon resonance spectroscopy and electrophoretic gel shift methods. Formation of the hMutLalpha.hMutSalpha.heteroduplex complex requi ... Full text Link to item Cite

Redundant exonuclease involvement in Escherichia coli methyl-directed mismatch repair.

Journal Article J Biol Chem · August 17, 2001 Previous biochemical analysis of Escherichia coli methyl-directed mismatch repair implicates three redundant single-strand DNA-specific exonucleases (RecJ, ExoI, and ExoVII) and at least one additional unknown exonuclease in the excision reaction (Cooper, ... Full text Link to item Cite

In vivo requirement for RecJ, ExoVII, ExoI, and ExoX in methyl-directed mismatch repair.

Journal Article Proc Natl Acad Sci U S A · June 5, 2001 Biochemical studies with model DNA heteroduplexes have implicated RecJ exonuclease, exonuclease VII, exonuclease I, and exonuclease X in Escherichia coli methyl-directed mismatch correction. However, strains deficient in the four exonucleases display only ... Full text Link to item Cite

Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability.

Journal Article Oncogene · April 27, 2000 Inactivation of DNA-mismatch repair underlies the genesis of microsatellite unstable (MSI) colon cancers. hPMS2 is one of several genes encoding components of the DNA-mismatch repair complex, and germline hPMS2 mutations have been found in a few kindreds w ... Full text Link to item Cite

The MutL ATPase is required for mismatch repair.

Journal Article J Biol Chem · March 31, 2000 Members of the MutL family contain a novel nucleotide binding motif near their amino terminus, and the Escherichia coli protein has been found to be a weak ATPase (Ban, C., and Yang, W. (1998) Cell 95, 541-552). Genetic analysis has indicated that substitu ... Full text Link to item Cite

Modulation of MutS ATP hydrolysis by DNA cofactors.

Journal Article Biochemistry · March 21, 2000 Escherichia coli MutS protein, which is required for mismatch repair, has a slow ATPase activity that obeys Michalelis-Menten kinetics. At 37 degrees C, the steady-state turnover rate for ATP hydrolysis is 1.0 +/- 0.3 min(-1) per monomer equivalent with a ... Full text Link to item Cite

Identifying sequence similarities between DNA molecules.

Journal Article Ultramicroscopy · February 2000 An atomic force microscope (AFM) imaging technique is described to compare sequences between two different DNA molecules and precisely locate nonhomologies in DNA strands. Sequence comparisons are made by forming heteroduplexes between the two molecules an ... Full text Link to item Cite

The kinetic mechanism of EcoRI endonuclease.

Journal Article J Biol Chem · November 5, 1999 Steady-state parameters governing cleavage of pBR322 DNA by EcoRI endonuclease are highly sensitive to ionic environment, with K(m) and k(cat) increasing 1,000-fold and 15-fold, respectively, when ionic strength is increased from 0.059 to 0.23 M. By contra ... Full text Link to item Cite

hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage.

Journal Article Proc Natl Acad Sci U S A · October 26, 1999 hMSH2.hMSH6 heterodimer (hMutSalpha) and hMLH1.hPMS2 complex (hMutLalpha) have been implicated in the cytotoxic response of mammalian cells to a number of DNA-damaging compounds, including methylating agents that produce O(6)-methylguanine (O(6)MeG) adduct ... Full text Link to item Cite

Repair of large insertion/deletion heterologies in human nuclear extracts is directed by a 5' single-strand break and is independent of the mismatch repair system.

Journal Article J Biol Chem · March 12, 1999 The repair of 12-, 27-, 62-, and 216-nucleotide unpaired insertion/deletion heterologies has been demonstrated in nuclear extracts of human cells. When present in covalently closed circular heteroduplexes or heteroduplexes containing a single-strand break ... Full text Link to item Cite

Modulation of cyclophosphamide activity by O6-alkylguanine-DNA alkyltransferase.

Journal Article Cancer Chemother Pharmacol · 1999 PURPOSE: The human medulloblastoma cell line D283 Med (4-HCR), a line resistant to 4-hydroperoxycyclophosphamide (4-HC), displays enhanced repair of DNA interstrand crosslinks induced by phosphoramide mustard. D283 Med (4-HCR) cells are cross-resistant to ... Full text Link to item Cite

Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR).

Journal Article Cancer Chemother Pharmacol · 1999 PURPOSE: We have previously reported preferential repair of DNA interstrand crosslinks in the 4-hydroperoxycyclophosphamide-resistant human medulloblastoma cell line D-283 Med (4-HCR). We now report further studies that explored the potential mechanisms un ... Full text Link to item Cite

DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma.

Journal Article J Clin Oncol · December 1998 Featured Publication PURPOSE: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA ... Full text Link to item Cite

Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism.

Journal Article J Biol Chem · November 27, 1998 ATP hydrolysis by bacterial and eukaryotic MutS activities is required for their function in mismatch correction, and two different models for the role of ATP in MutS function have been proposed. In the translocation model, based on study of bacterial MutS ... Full text Link to item Cite

DNA-dependent activation of the hMutSalpha ATPase.

Journal Article J Biol Chem · November 27, 1998 ATP hydrolysis by MutS homologs is required for function of these proteins in mismatch repair. However, the function of ATP hydrolysis in the repair reaction is controversial. In this paper we describe a steady-state kinetic analysis of the DNA-activated A ... Full text Link to item Cite

Isolation of MutSbeta from human cells and comparison of the mismatch repair specificities of MutSbeta and MutSalpha.

Journal Article J Biol Chem · July 31, 1998 A human MSH2-human MSH3 (hMSH2.hMSH3) complex of approximately 1:1 stoichiometry (human MutSbeta (hMutSbeta)) has been demonstrated in several human tumor cell lines and purified to near homogeneity. In vitro, hMutSbeta supports the efficient repair of ins ... Full text Link to item Cite

Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.

Journal Article Proc Natl Acad Sci U S A · July 21, 1998 Featured Publication Mutations of DNA mismatch repair genes, including the hMLH1 gene, have been linked to human colon and other cancers in which defective DNA repair is evidenced by the associated instability of DNA microsatellite sequences (MSI). Germ-line hMLH1 mutations ar ... Full text Link to item Cite

Analysis of DNA mismatch repair proteins in human medulloblastoma.

Journal Article Clin Cancer Res · June 1998 During replication, the primary function of the eukaryotic DNA mismatch repair (MMR) system is to recognize and correct mismatched base pairs within the DNA helix. Deficiencies in MMR have been reported previously in cases of hereditary nonpolyposis colore ... Link to item Cite

Mismatch-, MutS-, MutL-, and helicase II-dependent unwinding from the single-strand break of an incised heteroduplex.

Journal Article J Biol Chem · April 10, 1998 Escherichia coli MutS, MutL, and DNA helicase II are sufficient to initiate mismatch-dependent unwinding of an incised heteroduplex (Yamaguchi, M., Dao, V., and Modrich, P. (1998) J. Biol. Chem., 273, 9197-9201). We have studied unwinding of 6.4-kilobase c ... Full text Link to item Cite

MutS and MutL activate DNA helicase II in a mismatch-dependent manner.

Journal Article J Biol Chem · April 10, 1998 MutS, MutL, and DNA helicase II are required for the mismatch-provoked excision step that occurs during Escherichia coli methyl-directed mismatch repair. In this study MutL is shown to enhance the unwinding activity of DNA helicase II more than 10-fold on ... Full text Link to item Cite

Increased transversions in a novel mutator colon cancer cell line.

Journal Article Oncogene · March 5, 1998 We describe a novel mutator phenotype in the Vaco411 colon cancer cell line which increases the spontaneous mutation rate 10-100-fold over background. This mutator results primarily in transversion base substitutions which are found infrequently in repair ... Full text Link to item Cite

A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.

Journal Article Mol Cell Biol · March 1998 Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the me ... Full text Link to item Cite

Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors.

Journal Article Cancer Chemother Pharmacol · 1998 Featured Publication PURPOSE: The activity of vinorellbine, a new semisynthetic vinca alkaloid, was evaluated against a battery of human tumor xenografts derived from adult and pediatric CNS malignancies. METHODS: Tumors included adult high-grade gliomas (D-54 MG, D-245 MG), c ... Full text Link to item Cite

MutSα MutSβ, MutLα and DNA polymerase ôin human mismatch repair

Journal Article FASEB Journal · December 1, 1997 The human mismatch repair system corrects the eight hase-hase mismatches and insertion/deletion loops of 1-10 nucleotides. Using an in vitro assay, we have screened extracts from twenty-two cell lines derived from sporadic and hereditary RER (replication e ... Cite

Methotrexate-inducfd amplification of the human DHHFR/MSH3 region alters the ratio of mutsd and mutsβ and reduces the efficacy of base-base mismatch repair

Journal Article FASEB Journal · December 1, 1997 We examined the expression and fate of human MSH3 in the promyelocytic leukemia cell lines HI.-60 and HL-60R, where HL-60R is resistant to methotrexate by virtue of a DNA amplification event that includes the dihydrolblate reductase (DHFR) gene. This gene ... Cite

DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair.

Journal Article Proc Natl Acad Sci U S A · September 16, 1997 The level and fate of hMSH3 (human MutS homolog 3) were examined in the promyelocytic leukemia cell line HL-60 and its methotrexate-resistant derivative HL-60R, which is drug resistant by virtue of an amplification event that spans the dihydrofolate reduct ... Full text Link to item Cite

MutS mediates heteroduplex loop formation by a translocation mechanism.

Journal Article EMBO J · July 16, 1997 Interaction of Escherichia coli MutS and MutL with heteroduplex DNA has been visualized by electron microscopy. In a reaction dependent on ATP hydrolysis, complexes between a MutS dimer and a DNA heteroduplex are converted to protein-stabilized, alpha-shap ... Full text Link to item Cite

Methylator resistance mediated by mismatch repair deficiency in a glioblastoma multiforme xenograft.

Journal Article Cancer Res · July 15, 1997 A methylator-resistant human glioblastoma multiforme xenograft, D-245 MG (PR), in athymic nude mice was established by serially treating the parent xenograft D-245 MG with procarbazine. D-245 MG xenografts were sensitive to procarbazine, temozolomide, N-me ... Link to item Cite

Removal of polymerase-produced mutant sequences from PCR products.

Journal Article Proc Natl Acad Sci U S A · June 24, 1997 Heteroduplex DNA lacking d(GATC) methylation is subject to mismatch-provoked double-strand cleavage at d(GATC) sites in a reaction dependent on MutH, MutL, MutS, and ATP. We have exploited this reaction to develop a method for removal of polymerase-produce ... Full text Link to item Cite

Mapping individual cosmid DNAs by direct AFM imaging.

Journal Article Genomics · May 1, 1997 Individual cosmid clones have been restriction mapped by directly imaging, with the atomic force microscope (AFM), a mutant EcoRI endonuclease site-specifically bound to DNA. Images and data are presented that locate six restriction sites, predicted from g ... Full text Link to item Cite

DNA polymerase delta is required for human mismatch repair in vitro.

Journal Article J Biol Chem · April 18, 1997 HeLa nuclear extract was resolved into a depleted fraction incapable of supporting mismatch repair in vitro, and repair activity was restored upon the addition of a purified fraction isolated from HeLa cells by in vitro complementation assay. The highly en ... Full text Link to item Cite

Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems.

Journal Article Mol Cell Biol · February 1997 Nucleotide excision repair and the long-patch mismatch repair systems correct abnormal DNA structures arising from DNA damage and replication errors, respectively. DNA synthesis past a damaged base (translesion replication) often causes misincorporation at ... Full text Link to item Cite

Hmutlα and hmutsα in human mismatch repair

Journal Article FASEB Journal · December 1, 1996 Strand-specific mismatch correction in human cells occurs by a mechanism similar to that of the E. coli reaction, and like the bacterial pathway, the human system functions in mutation avoidance. Using an in vitro assay, we have identified mismatch repair ... Cite

Direct atomic force microscope imaging of EcoRI endonuclease site specifically bound to plasmid DNA molecules.

Journal Article Proc Natl Acad Sci U S A · August 20, 1996 Direct imaging with the atomic force microscope has been used to identify specific nucleotide sequences in plasmid DNA molecules. This was accomplished using EcoRI (Gln-111), a mutant of the restriction enzyme that has a 1000-fold greater binding affinity ... Full text Link to item Cite

Cisplatin and adriamycin resistance are associated with MutLalpha and mismatch repair deficiency in an ovarian tumor cell line.

Journal Article J Biol Chem · August 16, 1996 In contrast to parental A2780 ovarian tumor cells, extracts of one doxorubicin-resistant and two independent cis-diamminedichloroplatinum(II)-resistant derivatives are defective in strand-specific mismatch repair. The repair defect of the three hypermutabl ... Full text Link to item Cite

Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct.

Journal Article Proc Natl Acad Sci U S A · June 25, 1996 Bacterial and mammalian mismatch repair systems have been implicated in the cellular response to certain types of DNA damage, and genetic defects in this pathway are known to confer resistance to the cytotoxic effects of DNA-methylating agents. Such observ ... Full text Link to item Cite

Mutation detection with MutH, MutL, and MutS mismatch repair proteins.

Journal Article Proc Natl Acad Sci U S A · April 30, 1996 Escherichia coli methyl-directed mismatch repair is initiated by MutS-, MutL-, and ATP-dependent activation of MutH endonuclease, which cleaves at d(GATC) sites in the vicinity of a mismatch. This reaction provides an efficient method for detection of mism ... Full text Link to item Cite

Diverse hypermutability of multiple expressed sequence motifs present in a cancer with microsatellite instability.

Journal Article Oncogene · April 4, 1996 Colon cancer and an increasing number of other cancers have been found to exhibit instability of DNA microsatellite sequences. Such tumors have been designated as replication errors (RER) tumors. However, as microsatellites are only rarely found within cod ... Link to item Cite

MSH6, a Saccharomyces cerevisiae protein that binds to mismatches as a heterodimer with MSH2.

Journal Article Curr Biol · April 1, 1996 The process of post-replicative DNA-mismatch repair seems to be highly evolutionarily conserved. In Escherichia coli, DNA mismatches are recognized by the MutS protein. Homologues of the E. coli mutS and mutL mismatch-repair genes have been identified in o ... Full text Link to item Cite

Mismatch repair in replication fidelity, genetic recombination, and cancer biology.

Journal Article Annu Rev Biochem · 1996 Mismatch repair stabilizes the cellular genome by correcting DNA replication errors and by blocking recombination events between divergent DNA sequences. The reaction responsible for strand-specific correction of mispaired bases has been highly conserved d ... Full text Link to item Cite

A structural basis for a phosphoramide mustard-induced DNA interstrand cross-link at 5'-d(GAC).

Journal Article Proc Natl Acad Sci U S A · December 19, 1995 Phosphoramide mustard-induced DNA interstrand cross-links were studied both in vitro and by computer simulation. The local determinants for the formation of phosphoramide mustard-induced DNA interstrand cross-links were defined by using different pairs of ... Full text Link to item Cite

A Human Protein with Antimutator Activity

Journal Article Japanese Journal of Cancer Research · December 1, 1995 Full text Cite

Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells.

Journal Article Science · June 30, 1995 A mismatch-binding heterodimer of hMSH2 and a 160-kilodalton polypeptide has been isolated from HeLa cells by virtue of its ability to restore mismatch repair to nuclear extracts of hMSH2-deficient LoVo colorectal tumor cells. This heterodimer, designated ... Full text Link to item Cite

Mismatch repair deficiency in phenotypically normal human cells.

Journal Article Science · May 5, 1995 Tumor cells in patients with hereditary nonpolyposis colorectal cancer (HNPCC) are characterized by a genetic hypermutability caused by defects in DNA mismatch repair. A subset of HNPCC patients was found to have widespread mutations not only in their tumo ... Full text Link to item Cite

Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs.

Journal Article Proc Natl Acad Sci U S A · March 14, 1995 Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the hMLH1 gene. We have purified to near homogeneity an activity from HeLa cells that complements H6 nuclear extracts to restore rep ... Full text Link to item Cite

A human protein with antimutator activity.

Journal Article Jpn J Cancer Res · February 1995 Link to item Cite

Mismatch repair, genetic stability and tumour avoidance.

Journal Article Philos Trans R Soc Lond B Biol Sci · January 30, 1995 Escherichia coli methyl-directed mismatch repair eliminates premutagenic lesions that arise via DNA biosynthetic errors; components of the repair system also block ectopic recombination between diverged DNA sequences. A mismatch-dependent, methyl-directed ... Full text Link to item Cite

Mapping site-specific endonuclease binding to DNA by direct imaging with atomic force microscopy (AFM)

Journal Article Proceedings of SPIE - The International Society for Optical Engineering · January 1, 1995 Physical mapping of DNA can be accomplished by direct AFM imaging of site specific proteins bound to DNA molecules. Using Gln-111, a mutant of EcoRI endonuclease with a specific affinity for EcoRI sites 1000 times greater than wild type enzyme but with cle ... Full text Cite

Mismatch repair, genetic stability, and cancer.

Journal Article Science · December 23, 1994 Full text Link to item Cite

Misincorporation and mispaired primer extension by human immunodeficiency virus reverse transcriptase.

Journal Article J Biol Chem · September 30, 1994 Pre-steady-state methods were used to study the fidelity of human immunodeficiency virus reverse transcriptase. Fidelity of DNA-directed DNA synthesis can be attributed to a 1-2 order of magnitude reduction in affinity for noncomplementary dNTPs, and a 1-4 ... Link to item Cite

Mismatch repair proteins MutS and MutL inhibit RecA-catalyzed strand transfer between diverged DNAs.

Journal Article Proc Natl Acad Sci U S A · April 12, 1994 Bacterial mutS and mutL mutations confer large increases in recombination between sequences that are divergent by several percent at the nucleotide level, an effect attributed to a role for products of these genes in control of recombination fidelity. Sinc ... Full text Link to item Cite

Hypermutability and mismatch repair deficiency in RER+ tumor cells.

Journal Article Cell · December 17, 1993 A subset of sporadic colorectal tumors and most tumors developing in hereditary nonpolyposis colorectal cancer patients display frequent alterations in microsatellite sequences. Such tumors have been thought to manifest replication errors (RER+), but the b ... Full text Link to item Cite

Kinetic mechanism of the DNA-dependent DNA polymerase activity of human immunodeficiency virus reverse transcriptase.

Journal Article J Biol Chem · November 25, 1993 The kinetic pathway of DNA-dependent DNA polymerase activity of human immunodeficiency virus reverse transcriptase (HIV RT) as determined by pre-steady-state methods using a defined primer/template is as follows, [formula: see text] where E is RT, Dn,n+1 i ... Link to item Cite

An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair.

Journal Article Proc Natl Acad Sci U S A · July 15, 1993 The human lymphoblastoid MT1 B-cell line was previously isolated as one of a series of mutant cells able to survive the cytotoxic effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MT1 cells nevertheless remain sensitive to mutagenesis by MNNG and dis ... Full text Link to item Cite

Methyl-directed mismatch repair is bidirectional.

Journal Article J Biol Chem · June 5, 1993 Methyl-directed mismatch repair is initiated by the mismatch-provoked, MutHLS-dependent cleavage of the unmodified strand at a hemimethylated d(GATC) sequence. This reaction is independent of the polarity of the unmodified strand and can occur either 3' or ... Link to item Cite

Human strand-specific mismatch repair occurs by a bidirectional mechanism similar to that of the bacterial reaction.

Journal Article J Biol Chem · June 5, 1993 Nuclear extracts prepared from a HeLa cell line have been previously shown to support strand-specific repair of heteroduplex DNAs containing a site-specific, strand-specific incision (Holmes, J.J., Clark, S., and Modrich, P. (1990) Proc. Natl. Acad. Sci. U ... Link to item Cite

Bidirectional excision in methyl-directed mismatch repair.

Journal Article J Biol Chem · June 5, 1993 Using electron microscopy and indirect end-labeling methods, we have examined excision tracts produced by the Escherichia coli methyl-directed mismatch repair system on a closed circular G-T heteroduplex that contains a single d(GATC) site. Despite differi ... Link to item Cite

The DNA helicase activities of Rad3 protein of Saccharomyces cerevisiae and helicase II of Escherichia coli are differentially inhibited by covalent and noncovalent DNA modifications.

Journal Article J Biol Chem · May 15, 1993 Rad3 protein of Saccharomyces cerevisiae is a DNA-dependent ATPase that acts as a DNA helicase on partially duplex substrates. Rad3 protein is required for damage-specific incision of DNA during the nucleotide excision repair (NER) pathway in yeast. Helica ... Link to item Cite

Genomic mismatch scanning: a new approach to genetic linkage mapping.

Journal Article Nat Genet · May 1993 Genomic mismatch scanning (GMS) is a new method of genetic linkage analysis that does not require conventional polymorphic markers or gel electrophoresis. GMS is ideally suited to affected-relative-pair mapping. DNA fragments from all regions of identity-b ... Full text Link to item Cite

Mismatch repair and genetic stability in human cells.

Journal Article Cold Spring Harb Symp Quant Biol · 1993 Full text Link to item Cite

Initiation of methyl-directed mismatch repair.

Journal Article J Biol Chem · June 15, 1992 Escherichia coli MutH possesses an extremely weak d(GATC) endonuclease that responds to the state of methylation of the sequence (Welsh, K. M., Lu, A.-L., Clark, S., and Modrich, P. (1987) J. Biol. Chem. 262, 15624-15629). MutH endonuclease is activated in ... Link to item Cite

Strand-specific mismatch correction in nuclear extracts of human and Drosophila melanogaster cell lines.

Journal Article Proc Natl Acad Sci U S A · August 1990 Nuclear extracts derived from HeLa and Drosophila melanogaster KC cell lines have been found to correct single base-base mispairs within open circular DNA heteroduplexes containing a strand-specific, site-specific incision located 808 base pairs from the m ... Full text Link to item Cite

Escherichia coli mutY gene encodes an adenine glycosylase active on G-A mispairs.

Journal Article Proc Natl Acad Sci U S A · November 1989 Mutations in the mutY gene of Escherichia coli confer hypermutability reflecting G.C to T.A transversion mutations and result in a deficiency in methyl-independent G-A to G.C mismatch correction. In the present work, the mutY product has been purified to n ... Full text Link to item Cite

Glu-111 is required for activation of the DNA cleavage center of EcoRI endonuclease.

Journal Article J Biol Chem · July 15, 1989 Gap repair in the presence of 2'-deoxycytosine 5'-O-(1-thiotriphosphate) has been utilized to mutagenize the amino-terminal one-half of the structural gene for EcoRI endonuclease. This approach has led to identification of over 200 mutants defective in end ... Link to item Cite

The negative charge of Glu-111 is required to activate the cleavage center of EcoRI endonuclease.

Journal Article J Biol Chem · July 15, 1989 King et al. (King, K., Benkovic, S. J., and Modrich, P. (1989) 264, 11807-11815) have shown that Glu-111 is required for DNA cleavage by EcoRI endonuclease and have suggested that this residue is required for activation of the cleavage center upon specific ... Link to item Cite

DNA mismatch correction in a defined system.

Journal Article Science · July 14, 1989 DNA mismatch correction is a strand-specific process involving recognition of noncomplementary Watson-Crick nucleotide pairs and participation of widely separated DNA sites. The Escherichia coli methyl-directed reaction has been reconstituted in a purified ... Full text Link to item Cite

Methyl-directed DNA mismatch correction.

Journal Article J Biol Chem · April 25, 1989 In 1964 Robin Holliday (1) proposed the correction of DNA base pair mismatches within recombination intermediates as the basis for gene conversion. The existence of the mismatch repair systems implied by this proposal is now well established. Activities th ... Link to item Cite

Isolation and characterization of the Escherichia coli mutL gene product.

Journal Article J Biol Chem · January 15, 1989 The Escherichia coli mutL gene product has been purified to near homogeneity from an overproducing clone. The mutL locus encodes a polypeptide of 70,000 daltons as determined by denaturing gel electrophoresis. The native molecular weight of MutL protein as ... Link to item Cite

Gap formation is associated with methyl-directed mismatch correction under conditions of restricted DNA synthesis.

Journal Article Genome · 1989 A covalently closed, circular heteroduplex containing a G-T mismatch and a single hemimethylated d(GATC) site is subject to efficient methyl-directed mismatch correction in Escherichia coli extracts when repair DNA synthesis is severely restricted by limit ... Full text Link to item Cite

Escherichia coli mutY gene product is required for specific A-G----C.G mismatch correction.

Journal Article Proc Natl Acad Sci U S A · December 1988 A-G mispairs are subject to correction by two distinct pathways in cell-free extracts of Escherichia coli [Su, S.-S., Lahue, R.S., Au, K.G. & Modrich, P. (1988) J. Biol. Chem. 263, 6829-6835; Lu, A.-L. & Chang, D.Y. (1988) Genetics 118, 593-600]. One is th ... Full text Link to item Cite

Mismatch-containing oligonucleotide duplexes bound by the E. coli mutS-encoded protein.

Journal Article Nucleic Acids Res · August 25, 1988 The binding of the mutS gene product, a protein involved in at least two E. coli mismatch correction pathways, to a series of synthetic DNA duplexes containing mismatches or mismatch analogues of the purine/pyrimidine type was studied in order to establish ... Full text Link to item Cite

Mispair specificity of methyl-directed DNA mismatch correction in vitro.

Journal Article J Biol Chem · May 15, 1988 To evaluate the substrate specificity of methyl-directed mismatch repair in Escherichia coli extracts, we have constructed a set of DNA heteroduplexes, each of which contains one of the eight possible single base pair mismatches and a single hemimethylated ... Link to item Cite

Methyl-directed DNA mismatch repair in Escherichia coli.

Journal Article Mutat Res · March 1988 Some of the molecular aspects of methyl-directed mismatch repair in E. coli have been characterized. These include: mismatch recognition by mutS protein in which different mispairs are bound with different affinities; the direct involvement of d(GATC) site ... Full text Link to item Cite

Investigation of the complexes of EcoRI endonuclease with decanucleotides containing canonical and modified recognition sequences using fluorescence and optical detection of magnetic resonance spectroscopy.

Journal Article Biochim Biophys Acta · February 28, 1988 The binding of EcoRI endonuclease to the oligonucleotides d(GCGAATTCGC) and d(GCGAA) (5BrdU) (5BrdU) d(CGC) has been investigated to determine whether stacking interactions occur between tryptophan residues and the DNA bases. Fluorescence binding isotherms ... Full text Link to item Cite

Isolation and characterization of the Escherichia coli mutH gene product.

Journal Article J Biol Chem · November 15, 1987 The Escherichia coli mutH gene product has been isolated in near homogeneous form using an in vitro complementation assay for DNA mismatch correction (Lu, A.-L., Clark, S., and Modrich, P. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 4639-4643) which is depend ... Link to item Cite

Requirement for d(GATC) sequences in Escherichia coli mutHLS mismatch correction.

Journal Article Proc Natl Acad Sci U S A · March 1987 The involvement of d(GATC) sequences in Escherichia coli DNA mismatch correction was ascertained by analyzing in vitro repair efficiencies of a series of related, covalently closed circular DNA heteroduplexes that contained from zero to four d(GATC) sites. ... Full text Link to item Cite

DNA mismatch correction.

Journal Article Annu Rev Biochem · 1987 Full text Link to item Cite

Nucleotide sequence of a cDNA for a member of the human 90-kDa heat-shock protein family.

Journal Article Gene · 1987 This paper describes the isolation and sequence of a human cDNA homologous to a class of proteins commonly referred to as 90-kDa heat-shock proteins. The complete nucleotide sequence of 2563 bp and the deduced amino acid sequence are presented. A single lo ... Full text Link to item Cite

Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs.

Journal Article Proc Natl Acad Sci U S A · July 1986 The Escherichia coli mutS gene product is involved in mismatch correction in this organism. We have purified a biologically active form of the 97,000 Mr protein to near homogeneity from an overproducing strain. Enzymatic and chemical protection ("footprint ... Full text Link to item Cite

Mismatch correction.

Journal Article Basic Life Sci · 1986 Full text Link to item Cite

Facilitated diffusion during catalysis by EcoRI endonuclease. Nonspecific interactions in EcoRI catalysis.

Journal Article J Biol Chem · October 25, 1985 The potential for processive EcoRI endonuclease hydrolysis has been examined on several DNA substrates containing two EcoRI sites which were embedded in identical sequence environments. With a 388-base pair circular DNA, in which the two recognition sites ... Link to item Cite

In vitro maturation of circular bacteriophage P2 DNA. Purification of ter components and characterization of the reaction.

Journal Article J Biol Chem · June 10, 1985 The protein components required for generation of cohesive ends in vitro from circular bacteriophage P2 DNA have been purified to near homogeneity. In the presence of ATP, the purified products of P2 genes M and P together with empty phage capsids (compris ... Link to item Cite

Extent of equilibrium perturbation of the DNA helix upon enzymatic methylation of adenine residues.

Journal Article J Biol Chem · January 10, 1985 The extent of equilibrium perturbation of the DNA helix associated with enzymatic methylation of dA residues has been determined by the agarose gel electrophoresis band-shift method. Utilization of EcoRI methylase under conditions of reduced specificity to ... Link to item Cite

'Interactive' recognition in EcoRI restriction enzyme-DNA complex.

Journal Article Nucleic Acids Res · October 11, 1984 A solution study of interaction between DNA and EcoRI restriction enzyme shows that there is a definite distortion of DNA in the specific recognition complexes but no measurable DNA distortion in the non-specific interaction. ... Full text Link to item Cite

Prediction of secondary structure for Eco RI endonuclease.

Journal Article J Biol Chem · October 10, 1984 The circular dichroism of Eco RI restriction endonuclease was measured to 178 nm and analyzed for secondary structure. The results (33% alpha-helix, 25% beta-sheet, 17% turns, and 25% other structures) compare well with our joint prediction from sequence d ... Link to item Cite

Isolation of gram quantities of EcoRI restriction and modification enzymes from an overproducing strain.

Journal Article J Biol Chem · September 25, 1984 Structural genes for EcoRI restriction endonuclease and modification methylase have been inserted into the plasmid vector pKC30 (Shimatake, H., and Rosenberg, M. (1981) Nature (Lond.) 292, 128-132) downstream from the bacteriophage lambda pL promoter. Upon ... Link to item Cite

Partial NH2- and COOH-terminal sequence and cyanogen bromide peptide analysis of Escherichia coli sn-glycerol-3-phosphate acyltransferase.

Journal Article Journal of Biological Chemistry · September 25, 1983 The sn-glycerol-3-phosphate acyltransferase from Escherichia coli, an integral membrane protein whose activity is dependent on phospholipids, was purified to near homogeneity (Green, P. R., Merrill, A. H., Jr., and Bell, R. M., (1981) J. Biol. Chem. 256, 1 ... Cite

The DNA sequences encoding plsB and dgk loci of Escherichia coli.

Journal Article Journal of Biological Chemistry · September 25, 1983 We have determined the sequence of a 3865-base pair DNA segment from Escherichia coli containing plsB, the structural gene for the sn-glycerol-3-phosphate acyltransferase, and the dgk locus, believed to encode diglyceride kinase. The 806-amino acid sequenc ... Cite

Thermodynamic parameters governing interaction of EcoRI endonuclease with specific and nonspecific DNA sequences.

Journal Article J Biol Chem · August 25, 1983 Equilibrium binding of EcoRI endonuclease to DNA has been analyzed by nitrocellulose filter and preferential DNA cleavage methods. Association constants for pBR322 and a 34-base pair molecule containing the EcoRI site of this plasmid in a central position ... Link to item Cite

Methyl-directed repair of DNA base-pair mismatches in vitro.

Journal Article Proc Natl Acad Sci U S A · August 1983 An assay has been developed that permits analysis of DNA mismatch repair in cell-free extracts of Escherichia coli. The method relies on repair of heteroduplex molecules of f1 R229 DNA, which contain a base-pair mismatch within the single EcoRI site of the ... Full text Link to item Cite

Effects of high levels of DNA adenine methylation on methyl-directed mismatch repair in Escherichia coli.

Journal Article Genetics · August 1983 Two methods were used in an attempt to increase the efficiency and strand selectivity of methyl-directed mismatch repair of bacteriophage lambda heteroduplexes in E. coli. Previous studies of such repair used lambda DNA that was only partially methylated a ... Full text Link to item Cite

T7-induced DNA polymerase. Requirement for thioredoxin sulfhydryl groups.

Journal Article J Biol Chem · June 10, 1983 Bacteriophage T7-induced DNA polymerase is composed of a 1:1 complex of phage-induced gene 5 protein and Escherichia coli thioredoxin. Preparation of active subunits in the absence of sulfhydryl reagents indicates the reduced form of thioredoxin is suffici ... Link to item Cite

Positive-selection cloning vehicle useful for overproduction of hybrid proteins.

Journal Article J Bacteriol · May 1983 Plasmid pSCC31 contains the EcoRI endonuclease gene downstream from lambda pL. It does not yield transformants upon introduction into Escherichia coli unless the structural integrity of the endonuclease is destroyed. This makes it useful as a positive-sele ... Full text Link to item Cite

Involvement of outside DNA sequences in the major kinetic path by which EcoRI endonuclease locates and leaves its recognition sequence.

Journal Article Proc Natl Acad Sci U S A · July 1982 We have examined the kinetics of the interaction between endodeoxyribonuclease EcoRI (EC 3.1.23.13) and nine linear DNA fragments that range in size between 34 and 6,200 base pairs and contain the EcoRI site of plasmid pBR322 in a central location. The kin ... Full text Link to item Cite

Stereochemical course of nucleotidyl transfer catalyzed by bacteriophage T7 induced DNA polymerase.

Journal Article Biochemistry · May 11, 1982 The bacteriophage T7 induced DNA polymerase, consisting of the phage specified gene 5 protein associated with Escherichia coli thioredoxin, catalyzes the copolymerization of SP-dATP alpha S with dTTP, producing the alternating of polymer poly[dTs-A)] by a ... Full text Link to item Cite

Studies on sequence recognition by type II restriction and modification enzymes.

Journal Article CRC Crit Rev Biochem · 1982 Type II DNA restriction and modification systems are ideally suited for analysis of mechanisms by which proteins specifically recognize unique DNA sequences. Each system is comprised of a unique DNA recognition site and two enzymes, which in those cases ex ... Full text Link to item Cite

DNA determinants important in sequence recognition by Eco RI endonuclease.

Journal Article J Biol Chem · December 25, 1981 Alkylation interference and protection methods (Siebenlist, U., and Gilbert, W., (1980) Proc. Natl. Acad. Sci. U. S. A. 77, 122-126) have been utilized to deduce potential DNA contacts involved in specific complex formation between Eco RI endonuclease and ... Link to item Cite

Partial NH2- and cooh-terminal sequence analyses of Eco RI DNA restriction and modification enzymes.

Journal Article J Biol Chem · March 10, 1981 NH2- and COOH-terminal amino acid sequences of the Eco RI restriction and modification enzymes have been determined. The results allow localization of the coding regions within the DNA segment which controls activity of both enzymes. Processing of the endo ... Link to item Cite

Escherichia coli K-12 clones that overproduce dam methylase are hypermutable.

Journal Article J Bacteriol · January 1981 A strain of Escherichia coli K-12 that overproduces dam methylase 50-fold was found to be hypermutable, and mutations which resulted in loss of excess methylase activity restored mutation frequencies to wild-type levels. These results are consistent with i ... Full text Link to item Cite

Membrane phospholipid synthesis in Escherichia coli. Cloning of a structural gene (plsB) of the sn-glycerol-3-phosphate acyl/transferase.

Journal Article J Biol Chem · October 10, 1980 Si+ hybrid ColE1 plasmids of the Clarke-Carbon collection (Clarke, C., and Carbon, J. (1976) Cell 9, 91-99) which eliminate the sn-glycerol 3-phosphate growth requirement of a mutant of Escherichia coli with a Km defect in sn-glycerol-3-phosphate acyltrans ... Link to item Cite

Membrane phospholipid synthesis in Escherichia coli. Identification of the sn-glycerol-3-phosphate acyltransferase polypeptide as the plsB gene product.

Journal Article J Biol Chem · October 10, 1980 A collection of hybrid plasmids bearing a structural gene, plsB, for the sn-glycerol-3-phosphate acyltransferase of Escherichia cole (Lightner, V. A., Larson, T. J., Tailleur, P., Kantor, G. D., Raetz, C. R. H., Bell, R. M., and Modrich, P. (1980) J. Biol. ... Link to item Cite

Regulation of phospholipid biosynthesis in Escherichia coli. Cloning of the structural gene for the biosynthetic sn-glycerol-3-phosphate dehydrogenase.

Journal Article J Biol Chem · January 25, 1980 The structural gene for the Escherichia coli biosynthetic sn-glycerol-3-phosphate (glycerol-P) dehydrogenase gpsA, was transferred from a defective transducing phage (lambda dcysE, gpsA) into the Eco RI site of plasmid pMB9 by recombinant DNA techniques. T ... Link to item Cite

T7-induced DNA polymerase. Characterization of associated exonuclease activities and resolution into biologically active subunits.

Journal Article J Biol Chem · November 25, 1979 Bacteriophage T7-induced DNA polymerase has been isolated by a procedure suitable for large scale use and which yields near homogeneous enzyme. In addition to previously described DNA polymerase activity and 3' to 5' exonucleolytic activity on single stran ... Link to item Cite

Recognition sequence of the dam methylase of Escherichia coli K12 and mode of cleavage of Dpn I endonuclease.

Journal Article J Biol Chem · February 25, 1979 The recognition sequence for the dam methylase of Escherichia coli K12 has been determined directly by use of in vivo methylated ColE1 DNA or DNA methylated in vitro with purified enzyme. The methylase recognizes the symmetric tetranucleotide d(pG-A-T-C) a ... Link to item Cite

Substrate dependence of the mechanism of EcoRI endonuclease.

Journal Article Nucleic Acids Res · August 1978 The mechanism of EcoRI endonuclease is substrate dependent. At 37 degrees dissociation of the enzyme-Form II DNA intermediates of ColE1 DNA and bacteriophage G4 RFI DNA is negligible. Therefore, both DNA strands with in the EcoRI sequence are cleaved durin ... Full text Link to item Cite

Role of the 2-amino group of deoxyguanosine in sequence recognition by EcoRI restriction and modification enzymes.

Journal Article J Biol Chem · October 25, 1977 The dG residues within the EcoRI recognition sequence of ColE1 DNA have been selectively replaced with dI. Methylation of the altered sequence by the EcoRI modification enzyme is extremely slow as compared with methyl transfer to the natural recognition si ... Link to item Cite

EcoRI endonuclease. Physical and catalytic properties of the homogenous enzyme.

Journal Article J Biol Chem · October 10, 1976 A procedure for large scale isolation of Escherichia coli RI endonuclease in high yield has been developed. The purified enzyme is homogeneous as judged by polyacrylamide gel electrophoresis and analytical sedimentation. The denatured and reduced form of t ... Link to item Cite

Modification of Escherichia coli DNA ligase by cleavage with trypsin.

Journal Article J Biol Chem · June 10, 1976 Limited treatment of Escherichia coli DNA ligase with trypsin results in rapid loss of DNA joining activity. However, the ability to react with DPN to form the covalent enzyme-AMP intermediate is unaffected. The cleaved enzyme is also unable to catalyze th ... Link to item Cite

Bacteriophage T7 Deoxyribonucleic acid replication in vitro. A protein of Escherichia coli required for bacteriophage T7 DNA polymerase activity.

Journal Article J Biol Chem · July 25, 1975 In vivo, replication of T7 DNA does not occur after infection of Escherchia coli tsnC mutants (CHAMBERLIN, M. (1974) J. Virol. 14, 509-516). In vitro, extracts of tsnC mutant E. coli infected with T7 hage are incapable of replicating duplex T7 DNA, althoug ... Link to item Cite

Bacteriophage T7 deoxyribonucleic acid replication invitro. Bacteriophage T7 DNA polymerase: an an emzyme composed of phage- and host-specific subunits.

Journal Article J Biol Chem · July 25, 1975 The DNA polymerase induced after infection of Escherichia coli by phage T7 has been purified 500-fold to near homogeneity as judged by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The purified enzyme complements extracts of ... Link to item Cite

Enzymatic characterization of a mutant of Escherichia coli with an altered DNA ligase.

Journal Article Proc Natl Acad Sci U S A · May 1971 A temperature-sensitive, radiation-sensitive mutant of Escherichia coli has been assayed for DNA ligase activity in vitro. The strain contains a markedly reduced amount of DNA-joining activity, which is thermolabile. The formation of the ligase-adenylate i ... Full text Link to item Cite