The hMsh2-hMsh6 Complex Acts in Concert with Monoubiquitinated PCNA and Pol η in Response to Oxidative DNA Damage in Human Cells

Anastasia Zlatanou, Emmanuelle Despras, Tirzah Braz-Petta, Imenne Boubakour-Azzouz, Caroline Pouvelle, Grant S. Stewart, Satoshi Nakajima, Akira Yasui, Alexander A. Ishchenko, Patricia L. Kannouche

    Research output: Contribution to journalArticlepeer-review

    93 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)649-662
    Number of pages14
    JournalMolecular Cell
    Volume43
    Issue number4
    DOIs
    Publication statusPublished - 2011 Aug 19

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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