“…These results demonstrate that NPE efficiently recapitulates gap-directed, bi-directional MMR that is dependent on both MutSα/β and MutLα/β/γ. Some background repair observed in the absence of a gap could be due to either spontaneous base damages, which elicit base excision repair that in turn direct MMR ( Repmann et al, 2015 ), or strand breaks that have occurred during handling of the substrate. 10.7554/eLife.15155.003 Figure 1.…”
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
“…These results demonstrate that NPE efficiently recapitulates gap-directed, bi-directional MMR that is dependent on both MutSα/β and MutLα/β/γ. Some background repair observed in the absence of a gap could be due to either spontaneous base damages, which elicit base excision repair that in turn direct MMR ( Repmann et al, 2015 ), or strand breaks that have occurred during handling of the substrate. 10.7554/eLife.15155.003 Figure 1.…”
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
“…It could therefore be anticipated that only the subset of SSBs generated by the PARP1-dependent pathway will contribute to PARPi toxicity. However, our earlier findings demonstrated that SSBs generated not only during G o processing (26), but also those arising during uracil processing, a BER pathway postulated to be PARP1-independent, can be seen by mismatch repair (47). We would therefore argue that all BER-associated SSBs can potentially be channelled to HR and thus play a major role in the toxicity of PARPi in HR-deficient cells.…”
Section: Discussionmentioning
confidence: 98%
“…It had been postulated that these SSBs are not ‘visible’ to other pathways of DNA metabolism, because BER has been believed to proceed by a concerted, ‘passing the baton’ mechanism, in which the glycosylase hands over to the AP-endonuclease, which then hands over to the polymerase that then passes the final intermediate to the DNA ligase (25). We have shown earlier that this may not always be the case, given that SSBs generated during G o processing are visible to the mismatch repair system (26).…”
Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination (HR), but, in cells with suboptimal HR, PARP inhibition leads to genomic instability and cell death, a phenomenon currently exploited in the therapy of ovarian cancers in BRCA1/2 mutation carriers. In spite of their promise, resistance to PARP inhibitors (PARPis) has already emerged. In order to identify the possible underlying causes of the resistance, we set out to identify the endogenous source of DNA damage that activates PARPs. We argued that if the toxicity of PARPis is indeed caused by unrepaired SSBs, these breaks must arise spontaneously, because PARPis are used as single agents. We now show that a significant contributor to PARPi toxicity is oxygen metabolism. While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by depletion of OGG1 or MYH DNA glycosylases, as well as by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition. Thus, clinical resistance to PARPi therapy may emerge simply through reduced efficiency of oxidative damage repair.
“…Furthermore, it was shown that human MUTYH interacts with heterodimer MutSα via the hMSH6 subunit [64]. This interaction may facilitate MUTYHmediated excision of adenines opposite 8-oxoG and generation of single-strand breaks in the nascent strand which in turn can be used by MMR machinery as strand discrimination signals [65]. Thus the MUTYH-catalyzed repair activity is tightly controlled by the specific protein-protein interactions in order to reduce aberrant repair of the template strand during DNA replication.…”
Aerobic cellular respiration generates reactive oxygen species (ROS), which can damage macromolecules including lipids, proteins and DNA. It was proposed that aging is a consequence of accumulation naturally occurring unrepaired oxidative DNA damage. In human cells, on average approximately 2000 to 8000 DNA lesions occur per hour in each cell, or about 40000 to 200000 per cell per day. DNA repair systems are able to discriminate between regular and modified bases. For example, DNA glycosylases specifically recognize and excise damaged bases among vast majority of regular bases in the base excision repair (BER) pathway. However, mismatched pairs between two regular bases occur due to spontaneous conversion of 5-methylcytosine to thymine and DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved special DNA repair systems that target the non-damaged DNA strand in a duplex to remove mismatched regular DNA bases. Mismatch-specific adenine-and thymine-DNA glycosylases (MutY/MUTYH and TDG/MBD4, respectively) initiated base excision repair (BER) and mismatch repair (MMR) pathways can recognize and remove normal DNA bases in mismatched DNA duplexes. Paradoxically, under certain circumstances in DNA repair deficient cells bacterial MutY and human TDG can act in the aberrant manner: MutY and TDG removes Adenine and Thymine opposite misincorporated 8-oxoguanine and damaged Adenine, respectively. These unusual activities lead either to mutations or futile DNA repair, thus indicating that the DNA repair pathways which target non-damaged DNA strand can act in aberrant manner and introduce genome instability in the presence of unrepaired DNA lesions. Evidences gathered showing that in addition to the accumulation of oxidative DNA damage in cells, the aberrant DNA repair can also contribute to cancer, brain disorders and premature senescence. This review summarises the present knowledge about the aberrant DNA repair pathways for oxidised base modifications and their possible role in aging. K e y w o r d s: oxidative DNA damage; crystal structure; base excision repair; nucleotide incision repair; AP endonuclease.
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