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Endonucleolytic function of MutLalpha in human mismatch repair.

Publication ,  Journal Article
Kadyrov, FA; Dzantiev, L; Constantin, N; Modrich, P
Published in: 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 endonuclease that is activated in a mismatch-, MutSalpha-, RFC-, PCNA-, and ATP-dependent manner. Incision of a nicked mismatch-containing DNA heteroduplex by this four-protein system is strongly biased to the nicked strand. A mismatch-containing DNA segment spanned by two strand breaks is removed by the 5'-to-3' activity of MutSalpha-activated exonuclease I. The probable endonuclease active site has been localized to a PMS2 DQHA(X)(2)E(X)(4)E motif. This motif is conserved in eukaryotic PMS2 homologs and in MutL proteins from a number of bacterial species but is lacking in MutL proteins from bacteria that rely on d(GATC) methylation for strand discrimination in mismatch repair. Therefore, the mode of excision initiation may differ in these organisms.

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Published In

Cell

DOI

ISSN

0092-8674

Publication Date

July 28, 2006

Volume

126

Issue

2

Start / End Page

297 / 308

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Saccharomyces cerevisiae Proteins
  • Replication Protein C
  • Recombinant Proteins
  • Proliferating Cell Nuclear Antigen
  • MutS DNA Mismatch-Binding Protein
  • Models, Genetic
  • Humans
  • Exodeoxyribonucleases
  • Enzyme Activation
 

Citation

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Kadyrov, F. A., Dzantiev, L., Constantin, N., & Modrich, P. (2006). Endonucleolytic function of MutLalpha in human mismatch repair. Cell, 126(2), 297–308. https://doi.org/10.1016/j.cell.2006.05.039
Kadyrov, Farid A., Leonid Dzantiev, Nicoleta Constantin, and Paul Modrich. “Endonucleolytic function of MutLalpha in human mismatch repair.Cell 126, no. 2 (July 28, 2006): 297–308. https://doi.org/10.1016/j.cell.2006.05.039.
Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell. 2006 Jul 28;126(2):297–308.
Kadyrov, Farid A., et al. “Endonucleolytic function of MutLalpha in human mismatch repair.Cell, vol. 126, no. 2, July 2006, pp. 297–308. Pubmed, doi:10.1016/j.cell.2006.05.039.
Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell. 2006 Jul 28;126(2):297–308.
Journal cover image

Published In

Cell

DOI

ISSN

0092-8674

Publication Date

July 28, 2006

Volume

126

Issue

2

Start / End Page

297 / 308

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Saccharomyces cerevisiae Proteins
  • Replication Protein C
  • Recombinant Proteins
  • Proliferating Cell Nuclear Antigen
  • MutS DNA Mismatch-Binding Protein
  • Models, Genetic
  • Humans
  • Exodeoxyribonucleases
  • Enzyme Activation