MutSα maintains the mismatch repair capability by inhibiting PCNA unloading

Kawasoe, Yoshitaka; Tsurimoto, Toshiki; Nakagawa, Takuro; Masukata, Hisao; Takahashi, Tatsuro

doi:10.7554/elife.15155

Cited by 38 publications

(64 citation statements)

References 77 publications

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“…We observe that MutSα-dependent ICL repair has slower kinetics than the repair of mismatches in Xenopus extracts (Kawasoe et al, 2016; Radman, 2016). We surmise that the complexity of the ICL lesion, which requires two rounds of repair synthesis during RIR, could account for this difference.…”

Section: Discussionmentioning

confidence: 81%

“…First, we asked if the F411A substitution affected mismatch repair using a plasmid-based MMR assay in HSS extracts. We used plasmids containing a single A:C mismatch and a 15 nucleotide gap on the 3′ side of the A-strand (pMM1 AC ) to trigger gap-directed strand-specific MMR (Figure 2A), as previously described (Kawasoe et al, 2016). Repair of this plasmid occurs preferentially on the A-strand, and the correction of the A:C site to a G:C pair generates a BamHI restriction site (Figure 2A, top).…”

Section: Resultsmentioning

confidence: 99%

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Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway

et al. 2017

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SUMMARY DNA interstrand crosslinks (ICLs) that are repaired in non-dividing cells must be recognized independently of replication-associated DNA unwinding. Using cell-free extracts from Xenopus eggs that support neither replication nor transcription, we establish that ICLs are recognized and processed by the mismatch repair (MMR) machinery. We find that ICL repair requires MutSα (MSH2–MSH6) and the mismatch recognition FXE motif in MSH6, strongly suggesting that MutSα functions as an ICL sensor. MutSα recruits MutLα and EXO1 to ICL lesions, and the catalytic activity of both these nucleases is essential for ICL repair. As anticipated for a DNA unwinding-independent recognition process, we demonstrate that least distorting ICLs fail to be recognized and repaired by the MMR machinery. This establishes that ICL structure is a critical determinant of repair efficiency outside of DNA replication.

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Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway

et al. 2017

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“…Repair DNA synthesis completes the process. PCNA also binds MutSα, which seems to promote PCNA retention on chromatin after replication to facilitate MMR (Kawasoe et al, 2016). Intriguingly, PCNA phosphorylation at Y211 by EGFR was shown to inhibit binding of PCNA to MutS complexes, resulting in reduced MMR efficiency and increased mutagenesis (Ortega et al, 2015).…”

Section: Other Genome Stability Mechanismsmentioning

confidence: 99%

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

2017

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Proliferating Cell Nuclear Antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it. Through its many protein interactions and various post-translational modifications, PCNA has far-reaching impacts on a myriad of cellular functions.

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“…PCNA is an acidic polypeptide only synthesized and expressed in proliferating cells, and is additionally termed cyclin. As the auxiliary protein of DNA polymerase δ, PCNA is an important factor during cell synthesis (18)(19)(20). The expression of PCNA has been demonstrated to be associated with cell proliferation, and it acts as an indicator of cell proliferation (19).…”

Section: Discussionmentioning

confidence: 99%

Application of medical adhesive inhibits intimal hyperplasia involving the downregulation of ERK1/2 and eNOS levels

Chai

et al. 2018

Mol Med Report

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Vein graft remains the most broadly applied vascular material in coronary artery bypass surgery. However, the restenosis rate of the vein bridge following angioplasty is high. The present study investigated the effect of medical adhesive on vascular intimal hyperplasia, in addition to the signal transduction mechanism. A total of 36 New Zealand white rabbits were divided into three groups at random, including the normal group, the surgery group and the medical adhesive spray group. Following surgery for transplantation of the left external jugular vein to the ipsilateral common carotid artery for 4 weeks, the thickness and area of the intima and media of the vessel were measured on formalin‑fixed, paraffin wax‑embedded pathological sections using hematoxylin‑eosin staining, and alterations in the expression of proliferating cell nuclear antigen (PCNA), platelet endothelial cell adhesion molecule 1 (PECAM‑1), vascular cell adhesion protein 1 (VCAM‑1), extracellular signal‑regulated kinase (ERK)1/2, and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemical staining, reverse transcription‑quantitative polymerase chain reaction analysis and western blotting. The levels of intimal hyperplasia in the medical adhesive spray group were markedly decreased compared with the surgery group. Consistently, PCNA, PECAM‑1 and VCAM‑1 were underexpressed in the medical adhesive spray group compared with the surgery group. ERK1/2 and eNOS were underexpressed in the medical adhesive spray group compared with the surgery group. Therefore, the application of medical adhesive may inhibit intimal hyperplasia, which may be associated with the restriction of the over‑distension of the vein graft by downregulating the ERK1/2 and eNOS levels, reducing injury to the vascular intima and inhibiting the signaling pathway involved in intimal hyperplasia.

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MutSα maintains the mismatch repair capability by inhibiting PCNA unloading

Cited by 38 publications

References 77 publications

Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway

Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

Application of medical adhesive inhibits intimal hyperplasia involving the downregulation of ERK1/2 and eNOS levels

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