title: Mismatch repair protein MSH2 regulates translesion DNA synthesis following exposure of cells to UV radiation.
abstract: Translesion DNA synthesis (TLS) can use specialized DNA polymerases to insert and/or extend nucleotides across lesions, thereby limiting stalled replication fork collapse and the potential for cell death. Recent studies have shown that monoubiquitinated proliferating cell nuclear antigen (PCNA) plays an important role in recruitment of Y-family TLS polymerases to stalled replication forks after DNA damage treatment. To explore the possible roles of other factors that regulate the ultraviolet (UV)-induced assembly of specialized DNA polymerases at arrested replication forks, we performed immunoprecipitation experiments combined with mass spectrometry and established that DNA polymerase kappa (Polκ) can partner with MSH2, an important mismatch repair protein associated with hereditary non-polyposis colorectal cancer. We found that depletion of MSH2 impairs PCNA monoubiquitination and the formation of foci containing Polκ and other TLS polymerases after UV irradiation of cells. Interestingly, expression of MSH2 in Rad18-deficient cells increased UV-induced Polκ and REV1 focus formation without detectable changes in PCNA monoubiquitination, indicating that MSH2 can regulate post-UV focus formation by specialized DNA polymerases in both PCNA monoubiquitination-dependent and -independent fashions. Moreover, we observed that MSH2 can facilitate TLS across cyclobutane pyrimidine dimers photoproducts in living cells, presenting a novel role of MSH2 in post-UV cellular responses.
authors.affiliation: Laboratory of Cancer Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lingna
authors.initials: L
authors.lastname: Lv
authors.forename: Fengli
authors.initials: F
authors.lastname: Wang
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Ma
authors.forename: Yeran
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Liu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Errol C
authors.initials: EC
authors.lastname: Friedberg
authors.forename: Tie-Shan
authors.initials: TS
authors.lastname: Tang
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis*; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000032:analysis; D004259:DNA-Directed DNA Polymerase / Q000032:analysis / Q000378:metabolism; D006801:Humans; D051379:Mice; D051718:MutS Homolog 2 Protein / Q000378:metabolism / Q000502:physiology*; D009713:Nucleotidyltransferases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000378:metabolism; D051716:Replication Protein A / Q000032:analysis; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
chemical_list: D004247:DNA; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D051718:MutS Homolog 2 Protein; D009713:Nucleotidyltransferases; D018809:Proliferating Cell Nuclear Antigen; D011740:Pyrimidine Dimers; D051716:Replication Protein A; D044767:Ubiquitin-Protein Ligases; C485954:RAD18 protein, human; C498613:Polk protein, mouse; D000099270:Y-Family DNA Polymerases; C496086:Rev1 protein, mouse; C497172:MSH2 protein, human
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