title: The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol η in response to oxidative DNA damage in human cells.
abstract: Posttranslational modification of PCNA by ubiquitin plays an important role in coordinating the processes of DNA damage tolerance during DNA replication. The monoubiquitination of PCNA was shown to facilitate the switch between the replicative DNA polymerase with the low-fidelity polymerase eta (η) to bypass UV-induced DNA lesions during replication. Here, we show that in response to oxidative stress, PCNA becomes transiently monoubiquitinated in an S phase- and USP1-independent manner. Moreover, Polη interacts with mUb-PCNA at sites of oxidative DNA damage via its PCNA-binding and ubiquitin-binding motifs. Strikingly, while functional base excision repair is not required for this modification of PCNA or Polη recruitment to chromatin, the presence of hMsh2-hMsh6 is indispensable. Our findings highlight an alternative pathway in response to oxidative DNA damage that may coordinate the removal of oxidatively induced clustered DNA lesions and could explain the high levels of oxidized DNA lesions in MSH2-deficient cells.
authors.affiliation: Group TLS Polymerases and Cancer, Université Paris-Sud, CNRS-UMR8200, Institut Gustave Roussy, 94800 Villejuif, France.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zlatanou
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Despras
authors.forename: Tirzah
authors.initials: T
authors.lastname: Braz-Petta
authors.forename: Imenne
authors.initials: I
authors.lastname: Boubakour-Azzouz
authors.forename: Caroline
authors.initials: C
authors.lastname: Pouvelle
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakajima
authors.forename: Akira
authors.initials: A
authors.lastname: Yasui
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Ishchenko
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Kannouche
mesh_terms: D029681:Arabidopsis Proteins; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism / Q000502:physiology*; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism / Q000502:physiology*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination; D000076105:X-ray Repair Cross Complementing Protein 1; D000099270:Y-Family DNA Polymerases
chemical_list: D029681:Arabidopsis Proteins; D002843:Chromatin; D019951:DNA Polymerase beta; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D010450:Endopeptidases; D051718:MutS Homolog 2 Protein; D018809:Proliferating Cell Nuclear Antigen; D064570:Ubiquitin-Specific Proteases; D000076105:X-ray Repair Cross Complementing Protein 1; C094443:G-T mismatch-binding protein; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases; C579228:USP1 protein, human; C497172:MSH2 protein, human