Scholars@Duke
Lee Zou

Lee Zou

George Barth Geller Distinguished Professor
Pharmacology & Cancer Biology

Selected Publications

A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors.

Journal Article Clin Cancer Res · October 25, 2024 BACKGROUND: Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, gen ... Full text Link to item Cite

Regulation, functional impact, and therapeutic targeting of APOBEC3A in cancer.

Journal Article DNA Repair (Amst) · September 2024 Enzymes of the apolipoprotein B mRNA editing catalytic polypeptide like (APOBEC) family are cytosine deaminases that convert cytosine to uracil in DNA and RNA. Among these proteins, APOBEC3 sub-family members, APOBEC3A (A3A) and APOBEC3B (A3B), are promine ... Full text Link to item Cite

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors.

Journal Article Nat Commun · August 28, 2024 EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gen ... Full text Link to item Cite

Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.

Journal Article Mol Cell · June 6, 2024 Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, ... Full text Link to item Cite

Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.

Journal Article Nat Commun · February 21, 2024 Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed ... Full text Link to item Cite

APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability.

Journal Article Sci Adv · January 19, 2024 Mutation signatures associated with apolipoprotein B mRNA editing catalytic polypeptide-like 3A/B (APOBEC3A/B) cytidine deaminases are prevalent across cancers, implying their roles as mutagenic drivers during tumorigenesis and tumor evolution. APOBEC3A (A ... Full text Link to item Cite

ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.

Journal Article Mol Cell · October 19, 2023 The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is ... Full text Link to item Cite

ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.

Journal Article Genes Dev · October 1, 2023 The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target ... Full text Link to item Cite

Heterochromatin-Dependent Replication Stress: A Lesson from IDH1/2 Mutants.

Journal Article Cancer Res · September 15, 2023 Oncogenic point mutants of isocitrate dehydrogenases 1 and 2 (IDH2) generate 2-hydroxyglutarate, which inhibits lysine demethylases and increases heterochromatin. Tumor cells expressing IDH mutants are sensitive to PARP inhibitors (PARPi), offering an oppo ... Full text Link to item Cite

Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Journal Article Nature · August 2023 Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatm ... Full text Cite

ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms.

Journal Article Cell Rep · July 25, 2023 The ATR kinase safeguards genomic integrity during S phase, but how ATR protects DNA replication forks remains incompletely understood. Here, we combine four distinct assays to analyze ATR functions at ongoing and newly assembled replication forks upon rep ... Full text Link to item Cite

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.

Journal Article Nat Commun · January 17, 2023 Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perfor ... Full text Link to item Cite

TERRA and RAD51AP1 promote alternative lengthening of telomeres through an R- to D-loop switch.

Journal Article Mol Cell · November 3, 2022 Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop formation, but ALT also occurs through a RAD52-independent BIR pat ... Full text Link to item Cite

Protocol to stimulate and delineate alternative lengthening of telomeres in human U2OS cells.

Journal Article STAR Protoc · September 16, 2022 Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe a protocol to stimulate the formation of ALT-associated PML bodies (APBs) and ALT activity by tethering P ... Full text Link to item Cite

Sources, resolution and physiological relevance of R-loops and RNA-DNA hybrids.

Journal Article Nat Rev Mol Cell Biol · August 2022 RNA-DNA hybrids are generated during transcription, DNA replication and DNA repair and are crucial intermediates in these processes. When RNA-DNA hybrids are stably formed in double-stranded DNA, they displace one of the DNA strands and give rise to a thre ... Full text Link to item Cite

Hallmarks of DNA replication stress.

Journal Article Mol Cell · June 16, 2022 Faithful DNA replication is critical for the maintenance of genomic integrity. Although DNA replication machinery is highly accurate, the process of DNA replication is constantly challenged by DNA damage and other intrinsic and extrinsic stresses throughou ... Full text Link to item Cite

Translesion DNA synthesis mediates acquired resistance to olaparib plus temozolomide in small cell lung cancer.

Journal Article Sci Adv · May 13, 2022 In small cell lung cancer (SCLC), acquired resistance to DNA-damaging therapy is challenging to study because rebiopsy is rarely performed. We used patient-derived xenograft models, established before therapy and after progression, to dissect acquired resi ... Full text Link to item Cite

Oncogenic KIT Induces Replication Stress and Confers Cell Cycle Checkpoint Vulnerability in Melanoma.

Journal Article J Invest Dermatol · May 2022 Acral and mucosal melanomas arise from sun-protected sites, disproportionately impact darker-skinned individuals, and exact higher mortality than common types of cutaneous melanoma. Genetically, acral and mucosal melanomas harbor more alterations of KIT th ... Full text Link to item Cite

CDC7-independent G1/S transition revealed by targeted protein degradation.

Journal Article Nature · May 2022 The entry of mammalian cells into the DNA synthesis phase (S phase) represents a key event in cell division1. According to current models of the cell cycle, the kinase CDC7 constitutes an essential and rate-limiting trigger of DNA replication, acting toget ... Full text Link to item Cite

FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation.

Journal Article Proc Natl Acad Sci U S A · March 22, 2022 RNA modifications regulate a variety of cellular processes including DNA repair.The RNA methyltransferase TRDMT1 generates methyl-5-cytosine (m5C) on messen-ger RNA (mRNA) at DNA double-strand breaks (DSBs) in transcribed regions, pro-moting transcription- ... Full text Link to item Cite

Active RB causes visible changes in nuclear organization.

Journal Article J Cell Biol · March 7, 2022 RB restricts G1/S progression by inhibiting E2F. Here, we show that sustained expression of active RB, and prolonged G1 arrest, causes visible changes in chromosome architecture that are not directly associated with E2F inhibition. Using FISH probes agains ... Full text Link to item Cite

DNA repair defects in cancer and therapeutic opportunities.

Journal Article Genes Dev · March 1, 2022 DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repai ... Full text Link to item Cite

RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer.

Journal Article Sci Adv · February 18, 2022 Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prosta ... Full text Link to item Cite

RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair.

Journal Article Cell Rep · February 1, 2022 Single-stranded DNA (ssDNA) arising as an intermediate of cellular processes on DNA is a potential vulnerability of the genome unless it is appropriately protected. Recent evidence suggests that R-loops, consisting of ssDNA and DNA-RNA hybrids, can form in ... Full text Link to item Cite

An extending ATR-CHK1 circuitry: the replication stress response and beyond.

Journal Article Curr Opin Genet Dev · December 2021 The maintenance of genomic integrity relies on the coordination of a wide range of cellular processes and efficient repair of DNA damage. Since its discovery over two decades ago, the ATR kinase has been recognized as the master regulator of the circuitry ... Full text Link to item Cite

BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage.

Journal Article Nat Commun · October 13, 2021 The BRCA2 tumor suppressor protects genome integrity by promoting homologous recombination-based repair of DNA breaks, stability of stalled DNA replication forks and DNA damage-induced cell cycle checkpoints. BRCA2 deficient cells display the radio-resista ... Full text Link to item Cite

Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.

Journal Article Mol Cell · October 7, 2021 PRIMPOL repriming allows DNA replication to skip DNA lesions, leading to ssDNA gaps. These gaps must be filled to preserve genome stability. Using a DNA fiber approach to directly monitor gap filling, we studied the post-replicative mechanisms that fill th ... Full text Link to item Cite

The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells.

Journal Article Genes Dev · September 1, 2021 PARP inhibitor (PARPi) is widely used to treat BRCA1/2-deficient tumors, but why PARPi is more effective than other DNA-damaging drugs is unclear. Here, we show that PARPi generates DNA double-strand breaks (DSBs) predominantly in a trans cell cycle manner ... Full text Link to item Cite

Impacts of chromatin dynamics and compartmentalization on DNA repair.

Journal Article DNA Repair (Amst) · September 2021 The proper spatial organization of DNA, RNA, and proteins is critical for a variety of cellular processes. The genome is organized into numerous functional units, such as topologically associating domains (TADs), the formation of which is regulated by both ... Full text Link to item Cite

RNA transcripts stimulate homologous recombination by forming DR-loops.

Journal Article Nature · June 2021 Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) in the S and G2 phases of the cell cycle1-3. Several HR proteins are preferentially recruited to DSBs at transcriptionally active loci4-10, but how transcription promotes HR is poorly un ... Full text Link to item Cite

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer.

Journal Article Elife · April 23, 2021 The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and i ... Full text Link to item Cite

An extended APOBEC3A mutation signature in cancer.

Journal Article Nat Commun · March 11, 2021 APOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA. Recently, we showed that APOBEC3A (A3A) targets DNA hairpin loops. Here, we show that DNA secondary structure is in fact an orthogonal influence on A3A substra ... Full text Link to item Cite

Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.

Journal Article Mol Cell · March 4, 2021 Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we ind ... Full text Link to item Cite

CARM1 regulates replication fork speed and stress response by stimulating PARP1.

Journal Article Mol Cell · February 18, 2021 DNA replication forks use multiple mechanisms to deal with replication stress, but how the choice of mechanisms is made is still poorly understood. Here, we show that CARM1 associates with replication forks and reduces fork speed independently of its methy ... Full text Link to item Cite

Targeting the DNA replication stress phenotype of KRAS mutant cancer cells.

Journal Article Sci Rep · February 11, 2021 Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fibe ... Full text Link to item Cite

cGAS suppresses genomic instability as a decelerator of replication forks.

Journal Article Sci Adv · October 2020 The cyclic GMP-AMP synthase (cGAS), a sensor of cytosolic DNA, is critical for the innate immune response. Here, we show that loss of cGAS in untransformed and cancer cells results in uncontrolled DNA replication, hyperproliferation, and genomic instabilit ... Full text Link to item Cite

BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.

Journal Article Cancer Res · September 15, 2020 Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in ... Full text Link to item Cite

Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells.

Journal Article Sci Adv · July 2020 Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a ... Full text Link to item Cite

A genome-wide and cotranscriptional suppressor of R loops.

Journal Article Genes Dev · July 1, 2020 R loops arise from hybridization of RNA transcripts with template DNA during transcription. Unrepaired R loops lead to transcription-replication collisions, causing DNA damage and genomic instability. In this issue of Genes & Development, Pérez-Calero and ... Full text Link to item Cite

Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots.

Journal Article Nat Commun · June 12, 2020 APOBEC3A is a cytidine deaminase driving mutagenesis, DNA replication stress and DNA damage in cancer cells. While the APOBEC3A-induced vulnerability of cancers offers an opportunity for therapy, APOBEC3A protein and mRNA are difficult to quantify in tumor ... Full text Link to item Cite

m5C modification of mRNA serves a DNA damage code to promote homologous recombination.

Journal Article Nat Commun · June 5, 2020 Recruitment of DNA repair proteins to DNA damage sites is a critical step for DNA repair. Post-translational modifications of proteins at DNA damage sites serve as DNA damage codes to recruit specific DNA repair factors. Here, we show that mRNA is locally ... Full text Link to item Cite

An R-loop-initiated CSB-RAD52-POLD3 pathway suppresses ROS-induced telomeric DNA breaks.

Journal Article Nucleic Acids Res · February 20, 2020 Reactive oxygen species (ROS) inflict multiple types of lesions in DNA, threatening genomic integrity. How cells respond to ROS-induced DNA damage at telomeres is still largely unknown. Here, we show that ROS-induced DNA damage at telomeres triggers R-loop ... Full text Link to item Cite

ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop.

Journal Article Mol Cell · February 6, 2020 R loops arising during transcription induce genomic instability, but how cells respond to the R loop-associated genomic stress is still poorly understood. Here, we show that cells harboring high levels of R loops rely on the ATR kinase for survival. In res ... Full text Link to item Cite

Inhibition of ATR-Chk1 signaling blocks DNA double-strand-break repair and induces cytoplasmic vacuolization in metastatic osteosarcoma.

Journal Article Ther Adv Med Oncol · 2020 BACKGROUND: Ataxia-telangiectasia and Rad3 related protein kinase (ATR) is an essential regulator of the DNA damage response in various cancers; however, its expression and roles in osteosarcoma are unclear. We therefore chose to evaluate the significance ... Full text Link to item Cite

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks.

Journal Article Cell Biosci · 2020 To escape replicative senescence, cancer cells have to overcome telomere attrition during DNA replication. Most of cancers rely on telomerase to extend and maintain telomeres, but 4-11% of cancers use a homologous recombination-based pathway called alterna ... Full text Link to item Cite

Induction of BRCAness in Triple-Negative Breast Cancer by a CDK12/13 Inhibitor Improves Chemotherapy.

Journal Article Cancer Cell · November 11, 2019 In this issue of Cancer Cell, Quereda and colleagues report that a newly developed specific inhibitor of CDK12/13, SR-4835, sensitizes triple-negative breast cancer cells to PARP inhibitors and DNA-damaging chemotherapeutics by reducing expression of the g ... Full text Link to item Cite

The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition.

Journal Article Clin Cancer Res · October 15, 2019 PURPOSE: PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical probl ... Full text Link to item Cite

Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy.

Journal Article Oncologist · October 2019 BACKGROUND: Alterations in the DNA damage response (DDR) pathway confer sensitivity to certain chemotherapies, radiation, and other DNA damage repair targeted therapies. BRCA1/2 are the most well-studied DDR genes, but recurrent alterations are described i ... Full text Link to item Cite

Loss of Slug Compromises DNA Damage Repair and Accelerates Stem Cell Aging in Mammary Epithelium.

Journal Article Cell Rep · July 9, 2019 DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but also promote tissue aging. Because mice lacking Slug/Snai2 exhibit limited stem cell ac ... Full text Link to item Cite

Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma.

Journal Article Nat Commun · July 2, 2019 PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARP ... Full text Link to item Cite

Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features.

Journal Article Science · June 28, 2019 Cancer drivers require statistical modeling to distinguish them from passenger events, which accumulate during tumorigenesis but provide no fitness advantage to cancer cells. The discovery of driver genes and mutations relies on the assumption that exact p ... Full text Link to item Cite

Calcium Influx Guards Replication Forks against Exonuclease 1.

Journal Article Mol Cell · June 20, 2019 In this issue, Li et al. (2019) report a previously unknown Ca2+-CaMKK2-AMPK signaling cascade that protects stalled forks from degradation by phosphorylating and inhibiting the EXO1 nuclease, revealing a surprising role for Ca2+ influx in the maintenance ... Full text Link to item Cite

The BRUCE-ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development.

Journal Article Hepatology · June 2019 Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR (ataxia-telangiectasia mutated [ATM] and RAD3-related) is a master regulatory kinase that activates the re ... Full text Link to item Cite

Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways.

Journal Article Cell Rep · January 22, 2019 Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe an assay to visualize ALT-mediated telomeric DNA synthesis in ALT-associated PML bodies (APBs) without DN ... Full text Link to item Cite

Localized protein biotinylation at DNA damage sites identifies ZPET, a repressor of homologous recombination.

Journal Article Genes Dev · January 1, 2019 Numerous DNA repair and signaling proteins function at DNA damage sites to protect the genome. Here, we show that fusion of the promiscuous biotin ligase BirAR118G with RAD18 leads to localized protein biotinylation at DNA damage sites, allowing identifica ... Full text Link to item Cite

Getting a Genomic View of DNA Replication Stress.

Journal Article Mol Cell · October 18, 2018 DNA replication forks collapse at numerous sites throughout the genome under replication stress. Studies by Shastri et al. (2018) and Tubbs et al. (2018) used different genomics approaches to map the sites of replication fork collapse, revealing the contri ... Full text Link to item Cite

ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB.

Journal Article Nat Commun · October 8, 2018 Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a tran ... Full text Link to item Cite

Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes.

Journal Article Cancer Res · September 15, 2018 Heterozygous somatic mutations in spliceosome genes (U2AF1, SF3B1, ZRSR2, or SRSF2) occur in >50% of patients with myelodysplastic syndrome (MDS). These mutations occur early in disease development, suggesting that they contribute to MDS pathogenesis and m ... Full text Link to item Cite

A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation.

Journal Article Science · January 5, 2018 The ataxia telangiectasia mutated and Rad3-related (ATR) kinase is crucial for DNA damage and replication stress responses. Here, we describe an unexpected role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome m ... Full text Link to item Cite

E2F/DP Prevents Cell-Cycle Progression in Endocycling Fat Body Cells by Suppressing dATM Expression.

Journal Article Dev Cell · December 18, 2017 To understand the consequences of the complete elimination of E2F regulation, we profiled the proteome of Drosophila dDP mutants that lack functional E2F/DP complexes. The results uncovered changes in the larval fat body, a differentiated tissue that grows ... Full text Link to item Cite

MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells.

Journal Article Nat Commun · October 16, 2017 The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MR ... Full text Link to item Cite

Regulation of DNA break repair by transcription and RNA.

Journal Article Sci China Life Sci · October 2017 Repair of DNA double-strand breaks (DSBs) via the homologous recombination (HR) pathway is a highly regulated process. A number of proteins that participate in HR are intricately modulated by the cell cycle and chromatin environments of DSBs. Recent studie ... Full text Link to item Cite

A phosphorylation-and-ubiquitylation circuitry driving ATR activation and homologous recombination.

Journal Article Nucleic Acids Res · September 6, 2017 RPA-coated single-stranded DNA (RPA-ssDNA), a nucleoprotein structure induced by DNA damage, promotes ATR activation and homologous recombination (HR). RPA is hyper-phosphorylated and ubiquitylated after DNA damage. The ubiquitylation of RPA by PRP19 and R ... Full text Link to item Cite

APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition.

Journal Article Cancer Res · September 1, 2017 The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic site ... Full text Link to item Cite

Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers.

Journal Article J Clin Invest · May 1, 2017 Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor ge ... Full text Link to item Cite

RNA m6A methylation regulates the ultraviolet-induced DNA damage response.

Journal Article Nature · March 23, 2017 Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called th ... Full text Link to item Cite

Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1.

Journal Article Mol Cell · March 2, 2017 R loop, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA (ssDNA), has emerged as a major source of genomic instability. RNaseH1, which cleaves the RNA in RNA:DNA hybrids, plays an important role in R loop suppressio ... Full text Link to item Cite

ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells.

Journal Article Genes Dev · February 1, 2017 Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to ov ... Full text Link to item Cite

Coupling of Homologous Recombination and the Checkpoint by ATR.

Journal Article Mol Cell · January 19, 2017 ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end res ... Full text Link to item Cite

DNA Replication Checkpoint: New ATR Activator Identified.

Journal Article Curr Biol · January 9, 2017 The ATR kinase is a master regulator of replication stress responses. Four new studies show that the protein ETAA1 is an important activator of ATR in human cells, providing insights into how the ATR pathway reacts to replication stress. ... Full text Link to item Cite

A Zygotic Checkpoint for Unrepaired Lesions.

Journal Article Cell · December 15, 2016 DNA demethylation, a process involving DNA repair, is critical for reprogramming of the paternal genome during the oocyte-to-zygote transition. A new study by Ladstätter and Tachibana-Konwalski shows that a Chk1-mediated zygotic checkpoint monitors the coh ... Full text Link to item Cite

Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway.

Journal Article Annu Rev Genet · November 23, 2016 The ATR (ATM and rad3-related) pathway is crucial for proliferation, responding to DNA replication stress and DNA damage. This critical signaling pathway is carefully orchestrated through a multistep process requiring initial priming of ATR prior to damage ... Full text Link to item Cite

Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.

Journal Article Cancer Discov · July 2016 UNLABELLED: Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scal ... Full text Link to item Cite

The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation.

Journal Article J Biol Chem · January 1, 2016 The maintenance of genomic stability relies on the concerted action of DNA repair and DNA damage signaling pathways. The PIAS (protein inhibitor of activated STAT) family of SUMO (small ubiquitin-like modifier) ligases has been implicated in DNA repair, bu ... Full text Link to item Cite

Signaling of DNA replication stress through the ATR checkpoint

Chapter · January 1, 2016 DNA replication is one of the most fundamental cellular processes. Faithful replication of the entire genome is a daunting task, especially when cells are under intrinsic or extrinsic stress. To maintain genomic stability during DNA replication, eukaryotic ... Full text Cite

SCF(β-TRCP) promotes cell growth by targeting PR-Set7/Set8 for degradation.

Journal Article Nat Commun · December 15, 2015 The Set8/PR-Set7/KMT5a methyltransferase plays critical roles in governing transcriptional regulation, cell cycle progression and tumorigenesis. Although CRL4(Cdt2) was reported to regulate Set8 stability, deleting the PIP motif only led to partial resista ... Full text Link to item Cite

Molecular Pathways: Targeting ATR in Cancer Therapy.

Journal Article Clin Cancer Res · November 1, 2015 The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell-cycle ... Full text Link to item Cite

Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase.

Journal Article Mol Cell · September 17, 2015 The ATR-Chk1 pathway is critical for DNA damage responses and cell-cycle progression. Chk1 inhibition is more deleterious to cycling cells than ATR inhibition, raising questions about ATR and Chk1 functions in the absence of extrinsic replication stress. H ... Full text Link to item Cite

Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy.

Journal Article J Biol Chem · June 12, 2015 Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast c ... Full text Link to item Cite

Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.

Journal Article Science · January 16, 2015 Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically rem ... Full text Link to item Cite

Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance.

Journal Article Mol Cell · January 8, 2015 SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways. Noncovalent interactions of SLX4 with ubiquitin are required for localizing SLX4 to DNA interstrand crosslinks (ICLs), yet how SLX4 is targe ... Full text Link to item Cite

RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response.

Journal Article Cell Res · January 2015 The Replication Protein A (RPA) complex is an essential regulator of eukaryotic DNA metabolism. RPA avidly binds to single-stranded DNA (ssDNA) through multiple oligonucleotide/oligosaccharide-binding folds and coordinates the recruitment and exchange of g ... Full text Link to item Cite

The BRCA1-interacting protein Abraxas is required for genomic stability and tumor suppression.

Journal Article Cell Rep · August 7, 2014 Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C terminus (BRCT) domains interact with multiple proteins and are requ ... Full text Link to item Cite

SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway.

Journal Article Genes Dev · July 1, 2014 The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR-Chk1 kinase cascade, whether post-translational modification ... Full text Link to item Cite

Suppression of genome instability in pRB-deficient cells by enhancement of chromosome cohesion.

Journal Article Mol Cell · March 20, 2014 Chromosome instability (CIN), a common feature of solid tumors, promotes tumor evolution and increases drug resistance during therapy. We previously demonstrated that loss of the retinoblastoma protein (pRB) tumor suppressor causes changes in centromere st ... Full text Link to item Cite

PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry.

Journal Article Mol Cell · January 23, 2014 PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). Although the role for PRP19 in splicing is well characterized, its role in the DDR remains elusive. Through a proteomic screen for proteins that interact with RPA- ... Full text Link to item Cite

Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor.

Journal Article Carcinogenesis · November 2013 Inhibitors of poly(ADP-ribose) polymerase (PARP) are promising anticancer drugs, particularly for the treatment of tumors deficient in the DNA damage response (DDR). However, it is challenging to design effective therapeutic strategies for use of these com ... Full text Link to item Cite

EGFR-activating mutations correlate with a Fanconi anemia-like cellular phenotype that includes PARP inhibitor sensitivity.

Journal Article Cancer Res · October 15, 2013 In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remain ... Full text Link to item Cite

DNA damage sensing by the ATM and ATR kinases.

Journal Article Cold Spring Harb Perspect Biol · September 1, 2013 In eukaryotic cells, maintenance of genomic stability relies on the coordinated action of a network of cellular processes, including DNA replication, DNA repair, cell-cycle progression, and others. The DNA damage response (DDR) signaling pathway orchestrat ... Full text Link to item Cite

Two distinct modes of ATR activation orchestrated by Rad17 and Nbs1.

Journal Article Cell Rep · May 30, 2013 The ATM- and Rad3-related (ATR) kinase is a master regulator of the DNA damage response, yet how ATR is activated toward different substrates is still poorly understood. Here, we show that ATR phosphorylates Chk1 and RPA32 through distinct mechanisms at re ... Full text Link to item Cite

Detection of impaired homologous recombination repair in NSCLC cells and tissues.

Journal Article J Thorac Oncol · March 2013 INTRODUCTION: Homologous recombination repair (HRR) is a critical pathway for the repair of DNA damage caused by cisplatin or poly-ADP ribose polymerase (PARP) inhibitors. HRR may be impaired by multiple mechanisms in cancer, which complicates assessing th ... Full text Link to item Cite

Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling.

Journal Article Proc Natl Acad Sci U S A · February 5, 2013 The master checkpoint kinase ATR (ATM and Rad3-related) and its partner ATRIP (ATR-interacting protein) exist as a complex and function together in the DNA damage response. Unexpectedly, we found that the stability of the ATR-ATRIP complex is regulated by ... Full text Link to item Cite

Four pillars of the S-phase checkpoint.

Journal Article Genes Dev · February 1, 2013 The yeast Mec1 kinase is a key regulator of the DNA damage response (DDR). In this issue of Genes & Development, Kumar and Burgers (pp. 313-321) report that Ddc1, Dpb11, and Dna2 function in concert to activate Mec1 during S phase of the cell cycle. Furthe ... Full text Link to item Cite

The conserved C terminus of Claspin interacts with Rad9 and promotes rapid activation of Chk1.

Journal Article Cell Cycle · July 15, 2012 Claspin is a key mediator of the ATR-Chk1 checkpoint pathway. In response to DNA damage, Claspin interacts with Rad17 and Chk1 in a phosphorylation-dependent manner, enabling ATR to phosphorylate Chk1 efficiently. Claspin also interacts with Rad9, but how ... Full text Link to item Cite

Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response.

Journal Article Mol Cell · June 8, 2012 PCNA is a key component of DNA replication and repair machineries. DNA damage-induced PCNA ubiquitylation serves as a molecular mark to orchestrate postreplication repair. Here, we have identified and characterized Spartan, a protein that specifically reco ... Full text Link to item Cite

Direct role for proliferating cell nuclear antigen in substrate recognition by the E3 ubiquitin ligase CRL4Cdt2.

Journal Article J Biol Chem · March 30, 2012 The E3 ubiquitin ligase Cullin-ring ligase 4-Cdt2 (CRL4(Cdt2)) is emerging as an important cell cycle regulator that targets numerous proteins for destruction in S phase and after DNA damage, including Cdt1, p21, and Set8. CRL4(Cdt2) substrates contain a " ... Full text Link to item Cite

Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses.

Journal Article Proc Natl Acad Sci U S A · February 21, 2012 Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage respon ... Full text Link to item Cite

RPA and POT1: friends or foes at telomeres?

Journal Article Cell Cycle · February 15, 2012 Telomere maintenance in cycling cells relies on both DNA replication and capping by the protein complex shelterin. Two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomere 1 (POT1) play critical roles in DNA ... Full text Link to item Cite

NBS1 recruits RAD18 via a RAD6-like domain and regulates Pol η-dependent translesion DNA synthesis.

Journal Article Mol Cell · September 2, 2011 Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA dama ... Full text Link to item Cite

ATR autophosphorylation as a molecular switch for checkpoint activation.

Journal Article Mol Cell · July 22, 2011 The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master checkpoint regulator safeguarding the genome. Upon DNA damage, the ATR-ATRIP complex is recruited to sites of DNA damage by RPA-coated single-stranded DNA and activated by an elusi ... Full text Link to item Cite

Abstract 1358: Discovery and optimization of potent and selective benzonaphthyridinone analogs as dual mTOR/ATR small molecular inhibitors for treatment of cancer

Journal Article Cancer Research · April 15, 2011 AbstractThe Mammalian Target of Rapamycin is a highly conserved Serine/Threonine protein kinase that plays a key role in several fundamental cellular processes such as growth, proliferation and metabolism. A ... Full text Cite

TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.

Journal Article Nature · March 24, 2011 Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 ea ... Full text Link to item Cite

Regulation of homologous recombination by RNF20-dependent H2B ubiquitination.

Journal Article Mol Cell · March 4, 2011 The E3 ubiquitin ligase RNF20 regulates chromatin structure by monoubiquitinating histone H2B in transcription. Here, we show that RNF20 is localized to double-stranded DNA breaks (DSBs) independently of H2AX and is required for the DSB-induced H2B ubiquit ... Full text Link to item Cite

ATR: a master conductor of cellular responses to DNA replication stress.

Journal Article Trends Biochem Sci · March 2011 The integrity of the genome is constantly challenged by intrinsic and extrinsic genotoxic stresses that damage DNA. The cellular responses to DNA damage are orchestrated by DNA damage signaling pathways, also known as DNA damage checkpoints. These signalin ... Full text Link to item Cite

ATR-p53 restricts homologous recombination in response to replicative stress but does not limit DNA interstrand crosslink repair in lung cancer cells.

Journal Article PLoS One · 2011 Homologous recombination (HR) is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB). However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The ... Full text Link to item Cite

A human cell extract-based assay for the activation of ATM and ATR checkpoint kinases.

Journal Article Methods Mol Biol · 2011 The Ataxia telangiectasia-mutated (ATM) and the ATM-Rad3-related (ATR) kinases are master regulators of the DNA damage-signaling pathways that respond to a wide variety of DNA damage. In this chapter, we describe an in vitro biochemical assay to study the ... Full text Link to item Cite

CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase.

Journal Article Mol Cell · October 8, 2010 The proper coordination between DNA replication and mitosis during cell-cycle progression is crucial for genomic stability. During G2 and mitosis, Set8 catalyzes monomethylation of histone H4 on lysine 20 (H4K20me1), which promotes chromatin compaction. Se ... Full text Link to item Cite

Oligonucleotide/oligosaccharide-binding fold proteins: a growing family of genome guardians.

Journal Article Crit Rev Biochem Mol Biol · August 2010 The maintenance of genomic stability relies on the coordinated action of a number of cellular processes, including activation of the DNA-damage checkpoint, DNA replication, DNA repair, and telomere homeostasis. Many proteins involved in these cellular proc ... Full text Link to item Cite

The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response.

Journal Article Mol Cell · July 30, 2010 Cells from Fanconi anemia (FA) patients are extremely sensitive to DNA interstrand crosslinking (ICL) agents, but the molecular basis of the hypersensitivity remains to be explored. FANCM (FA complementation group M), and its binding partner, FAAP24, ancho ... Full text Link to item Cite

A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.

Journal Article Cell · April 2, 2010 Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we con ... Full text Link to item Cite

Checkpoint Mec-tivation comes in many flavors.

Journal Article Mol Cell · December 11, 2009 In this issue of Molecular Cell, Navadgi-Patil and Burgers show that the budding yeast Mec1 kinase is activated by DNA damage through two distinct Ddc1-mediated mechanisms during G1 and G2 phases of the cell cycle. ... Full text Link to item Cite

Prevalence and functional analysis of sequence variants in the ATR checkpoint mediator Claspin.

Journal Article Mol Cancer Res · September 2009 Mutational inactivation of genes controlling the DNA-damage response contributes to cancer susceptibility within families and within the general population as well as to sporadic tumorigenesis. Claspin (CLSPN) encodes a recently recognized mediator protein ... Full text Link to item Cite

Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks.

Journal Article Mol Cell · March 13, 2009 ATM and ATR are two master checkpoint kinases activated by double-stranded DNA breaks (DSBs). ATM is critical for the initial response and the subsequent ATR activation. Here we show that ATR activation is coupled with loss of ATM activation, an unexpected ... Full text Link to item Cite

ATR signaling at a glance.

Journal Article J Cell Sci · February 1, 2009 Full text Link to item Cite

Dual functions of DNA replication forks in checkpoint signaling and PCNA ubiquitination.

Journal Article Cell Cycle · January 15, 2009 During cell proliferation, DNA damage inflicted by intrinsic or extrinsic genotoxic stresses impose a threat to DNA replication. The stability of the DNA replication forks that encounter DNA damage is crucial for genomic integrity. Both the ATR-regulated c ... Full text Link to item Cite

Chk1 and Claspin potentiate PCNA ubiquitination.

Journal Article Genes Dev · May 1, 2008 Chk1 is a kinase crucial for genomic integrity and an effector of ATR (ATM and Rad3-related) in DNA damage response. Here, we show that Chk1 regulates the DNA damage-induced ubiquitination of proliferating cell nuclear antigen (PCNA), which facilitates the ... Full text Link to item Cite

Launching a ubiquitination cascade at DNA breaks.

Journal Article Proc Natl Acad Sci U S A · December 26, 2007 Full text Link to item Cite

Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress.

Journal Article Mol Cell · August 4, 2006 The ATR-mediated checkpoint is not only critical for responding to genotoxic stress but also essential for cell proliferation. The RFC-related checkpoint protein Rad17, a phosphorylation substrate of ATR, is critical for ATR-mediated checkpoint signaling a ... Full text Link to item Cite

ATRIP associates with replication protein A-coated ssDNA through multiple interactions.

Journal Article Proc Natl Acad Sci U S A · January 17, 2006 The ATR (ATM- and rad3-related)-mediated checkpoint pathway has a crucial role in regulating the cellular responses to DNA damage and DNA-replication stress. ATRIP (ATR-interacting protein), the regulatory partner of ATR, binds directly to replication prot ... Full text Link to item Cite

Recruitment of ATR-ATRIP, Rad17, and 9-1-1 complexes to DNA damage.

Journal Article Methods Enzymol · 2006 The ATR (ataxia-telangiectasia mutated and rad3-related)-ATRIP (ATR-interacting protein) kinase complex plays a central role in the checkpoint responses to a variety of types of DNA damage, especially those interfering with DNA replication. The checkpoint- ... Full text Link to item Cite

Checkpoint and coordinated cellular responses to DNA damage.

Journal Article Results Probl Cell Differ · 2006 The DNA damage and replication checkpoints are signaling mechanisms that regulate and coordinate cellular responses to genotoxic conditions. The activation of checkpoints not only attenuates cell cycle progression, but also facilitates DNA repair and recov ... Link to item Cite

Sensing, signaling, and responding to DNA damage: organization of the checkpoint pathways in mammalian cells.

Journal Article J Cell Biochem · February 1, 2005 The DNA damage and replication checkpoints are signaling mechanisms that regulate and coordinate cellular responses to genotoxic conditions. Unlike typical signal transduction mechanisms that respond to one or a few stimuli, checkpoints can be activated by ... Full text Link to item Cite

Replication protein A-mediated recruitment and activation of Rad17 complexes

Journal Article Proceedings of the National Academy of Sciences · November 25, 2003 The human Rad17–Rfc2-5 and Rad9–Rad1–Hus1 complexes play crucial roles in the activation of the ATR-mediated DNA damage and DNA replication stress response pathways. In response to DNA damage, Rad9 is recruited to chromatin in a Rad17- ... Full text Cite

Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes

Journal Article Science · June 6, 2003 The function of the ATR (ataxia-telangiectasia mutated– and Rad3-related)–ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Here, we show that replication ... Full text Cite

Checking on the fork: the DNA-replication stress-response pathway

Journal Article Trends in Cell Biology · November 2002 Full text Cite

Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin

Journal Article Genes & Development · January 15, 2002 Cells respond to DNA damage by activating a network of signaling pathways that control cell cycle progression and DNA repair. Genetic studies in yeast suggested that several checkpoint proteins, including the RFC-related Rad17 protein, and the PCNA ... Full text Cite

Using electrophoresis to observe the interaction of nitrogenase with ions.

Journal Article Electrophoresis · August 2000 The two protein components of nitrogenase from Klebsiella pneumoniae were shown to interact with metal ions and ADP, altering their electrophoretic mobility in polyacrylamide gel electrophoresis. Both Mg+2 and Mn+2 caused reduced mobility of Fe protein rel ... Full text Link to item Cite

Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase.

Journal Article Mol Cell Biol · May 2000 In Saccharomyces cerevisiae, replication origins are activated with characteristic timing during S phase. S-phase cyclin-dependent kinases (S-CDKs) and Cdc7p-Dbf4p kinase are required for origin activation throughout S phase. The activation of S-CDKs leads ... Full text Link to item Cite

Interaction with magnesium and ADP stabilizes both components of nitrogenase from Klebsiella pneumoniae against urea denaturation.

Journal Article Protein Sci · January 2000 The nitrogenase enzyme of Klebsiella pneumoniae consists of two separable proteins, each with multiple subunits and one or more oxygen sensitive metallocenters. The wild-type nitrogenase proteins are stable to electrophoresis in high concentrations of urea ... Full text Link to item Cite

Formation of a preinitiation complex by S-phase cyclin CDK-dependent loading of Cdc45p onto chromatin.

Journal Article Science · April 24, 1998 Cdc45p, a protein essential for initiation of DNA replication, associates with chromatin after "start" in late G1 and during the S phase of the cell cycle. Binding of Cdc45p to chromatin depends on Clb-Cdc28 kinase activity as well as functional Cdc6p and ... Full text Link to item Cite

CDC45, a novel yeast gene that functions with the origin recognition complex and Mcm proteins in initiation of DNA replication.

Journal Article Mol Cell Biol · February 1997 The CDC45 gene of Saccharomyces cerevisiae was isolated by complementation of the cold-sensitive cdc45-1 mutant and shown to be essential for cell viability. Although CDC45 genetically interacts with a group of MCM genes (CDC46, CDC47, and CDC54), the pred ... Full text Link to item Cite