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Werner syndrome protein interacts functionally with translesion DNA polymerases
- Kamath-Loeb, Ashwini S., Lan, Li, Nakajima, Satoshi, Yasui, Akira, Loeb, Lawrence A.
- Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.25 pp. 10394-10399
- DNA, DNA helicases, chromosome aberrations, irradiation, mutagenesis, neoplasms, nucleotides, polymerization
- Werner syndrome (WS) is characterized by premature onset of age-associated disorders and predisposition to cancer. The WS protein, WRN, encodes 3' [rightward arrow] 5' DNA helicase and 3' [rightward arrow] 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.