Werner syndrome protein interacts functionally with translesion DNA polymerases

Ashwini S. Kamath-Loeb, Li Lan, Satoshi Nakajima, Akira Yasui, Lawrence A. Loeb

    Research output: Contribution to journalArticlepeer-review

    50 Citations (Scopus)

    Abstract

    Werner syndrome (WS) is characterized by premature onset of age-associated disorders and predisposition to cancer. The WS protein, WRN, encodes 3′ → 5′ DNA helicase and 3′ → 5′ DNA exonuclease activities, and is implicated in the maintenance of genomic stability. Translesion (TLS) DNA polymerases (Pols) insert nucleotides opposite replication-blocking DNA lesions and presumably prevent replication fork stalling/collapse. Here, we present in vitro and in vivo data that demonstrate functional interaction between WRN and the TLS Pols, Polη, Polκ, and Polι. In vitro, WRN stimulates the extension activity of TLS Pols on lesion-free and lesion-containing DNA templates, and alleviates pausing at stalling lesions. Stimulation is mediated through an increase in the apparent Vmax of the polymerization reaction. Notably, by accelerating the rate of nucleotide incorporation, WRN increases mutagenesis by Polη. In vivo, WRN and Polη colocalize at replication-dependent foci in response to UVC irradiation. The functional interaction between WRN and TLS Pols may promote replication fork progression, at the expense of increased mutagenesis, and obviate the need to resolve stalled/collapsed forks by processes involving chromosomal rearrangements.

    Original languageEnglish
    Pages (from-to)10394-10399
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume104
    Issue number25
    DOIs
    Publication statusPublished - 2007 Jun 19

    Keywords

    • DNA damage
    • Mutagenesis

    ASJC Scopus subject areas

    • General

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