Evidence That the DNA Mismatch Repair System Removes 1-Nucleotide Okazaki Fragment Flaps

Kadyrova, Lyudmila Y.; Dahal, Basanta K.; Kadyrov, Farid A.

doi:10.1074/jbc.m115.660357

Cited by 12 publications

(11 citation statements)

References 75 publications

(99 reference statements)

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“…Hijacking PCNA from polymerases may not be overly deleterious to DNA synthesis, because new PCNA loading at the 3’-terminus would quickly restore the PCNA-polymerase complex. Similar hijacking might occur on other PCNA interactors such as CAF-1 and FEN-1, both of which are reported to show complex interplay with MutSα ( Kadyrova et al, 2011 ; Schöpf et al, 2012 ; Kadyrova et al, 2015 ; Liu et al, 2015 ). On the leading strand that has less PCNA, such competition could be important for effective MMR.…”

Section: Discussionmentioning

confidence: 62%

MutSα maintains the mismatch repair capability by inhibiting PCNA unloading

Kawasoe

Tsurimoto

Nakagawa

et al. 2016

eLife

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Eukaryotic mismatch repair (MMR) utilizes single-strand breaks as signals to target the strand to be repaired. DNA-bound PCNA is also presumed to direct MMR. The MMR capability must be limited to a post-replicative temporal window during which the signals are available. However, both identity of the signal(s) involved in the retention of this temporal window and the mechanism that maintains the MMR capability after DNA synthesis remain unclear. Using Xenopus egg extracts, we discovered a mechanism that ensures long-term retention of the MMR capability. We show that DNA-bound PCNA induces strand-specific MMR in the absence of strand discontinuities. Strikingly, MutSα inhibited PCNA unloading through its PCNA-interacting motif, thereby extending significantly the temporal window permissive to strand-specific MMR. Our data identify DNA-bound PCNA as the signal that enables strand discrimination after the disappearance of strand discontinuities, and uncover a novel role of MutSα in the retention of the post-replicative MMR capability.DOI: http://dx.doi.org/10.7554/eLife.15155.001

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Section: Discussionmentioning

confidence: 62%

MutSα maintains the mismatch repair capability by inhibiting PCNA unloading

Kawasoe

Tsurimoto

Nakagawa

et al. 2016

eLife

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“…The DNA mismatch repair (MMR) 2 system has been conserved from bacteria to humans as a consequence of its importance for the maintenance of genome stability (1-3). The MMR system has several activities that are involved in genome metabolism (1,(3)(4)(5)(6)(7)(8)(9)(10). The correction of DNA mismatches is the best understood activity of the MMR system.…”

mentioning

confidence: 99%

The Major Replicative Histone Chaperone CAF-1 Suppresses the Activity of the DNA Mismatch Repair System in the Cytotoxic Response to a DNA-methylating Agent

Kadyrova

Dahal

Kadyrov

2016

Journal of Biological Chemistry

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The DNA mismatch repair (MMR) system corrects DNA mismatches in the genome. It is also required for the cytotoxic response of O-methylguanine-DNA methyltransferase (MGMT)-deficient mammalian cells and yeast mgt1Δ rad52Δ cells to treatment with S1-type methylating agents, which produce cytotoxic O-methylguanine (O-mG) DNA lesions. Specifically, an activity of the MMR system causes degradation of irreparable O-mG-T mispair-containing DNA, triggering cell death; this process forms the basis of treatments of MGMT-deficient cancers with S1-type methylating drugs. Recent research supports the view that degradation of irreparable O-mG-T mispair-containing DNA by the MMR system and CAF-1-dependent packaging of the newly replicated DNA into nucleosomes are two concomitant processes that interact with each other. Here, we studied whether CAF-1 modulates the activity of the MMR system in the cytotoxic response to S1-type methylating agents. We found that CAF-1 suppresses the activity of the MMR system in the cytotoxic response of yeast mgt1Δ rad52Δ cells to the prototypic S1-type methylating agent N-methyl-N'-nitro-N-nitrosoguanidine. We also report evidence that in human MGMT-deficient cell-free extracts, CAF-1-dependent packaging of irreparable O-mG-T mispair-containing DNA into nucleosomes suppresses its degradation by the MMR system. Taken together, these findings suggest that CAF-1-dependent incorporation of irreparable O-mG-T mispair-containing DNA into nucleosomes suppresses its degradation by the MMR system, thereby defending the cell against killing by the S1-type methylating agent.

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“…The MMR system also corrects DNA mispairs containing 8-oxoguanine and other oxidatively damaged bases (17,30–33). Furthermore, the MMR system removes 1-nucleotide Okazaki fragment flaps (34) and single ribonucleotides, which are incorporated into DNA opposite noncomplementary deoxyribonucleotides (35). MutSα (MSH2-MSH6 heterodimer) and MutLα (MLH1-PMS2 heterodimer in humans and MLH1-PMS1 heterodimer in the yeast S. cerevisiae ) are required for the majority of MMR events in eukaryotes (28,36,37).…”

Section: Introductionmentioning

confidence: 99%

Endonuclease activities of MutLα and its homologs in DNA mismatch repair

Kadyrova

Kadyrov

2016

DNA Repair

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MutLα is a key component of the DNA mismatch repair system in eukaryotes. The DNA mismatch repair system has several genetic stabilization functions. Of these functions, DNA mismatch repair is the major one. The loss of MutLα abolishes DNA mismatch repair, thereby predisposing humans to cancer. MutLα has an endonuclease activity that is required for DNA mismatch repair. The endonuclease activity of MutLα depends on the DQHA(X)2E(X)4E motif which is a part of the active site of the nuclease. This motif is also present in many bacterial MutL and eukaryotic MutLγ proteins, DNA mismatch repair system factors that are homologous to MutLα. Recent studies have shown that yeast MutLγ and several MutL proteins containing the DQHA(X)2E(X)4E motif possess endonuclease activities. Here, we review the endonuclease activities of MutLα and its homologs in the context of DNA mismatch repair.

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Evidence That the DNA Mismatch Repair System Removes 1-Nucleotide Okazaki Fragment Flaps

Cited by 12 publications

References 75 publications

MutSα maintains the mismatch repair capability by inhibiting PCNA unloading

MutSα maintains the mismatch repair capability by inhibiting PCNA unloading

The Major Replicative Histone Chaperone CAF-1 Suppresses the Activity of the DNA Mismatch Repair System in the Cytotoxic Response to a DNA-methylating Agent

Endonuclease activities of MutLα and its homologs in DNA mismatch repair

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