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Chk2‐dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair
Author(s) -
Chou WenCheng,
Wang HuiChun,
Wong FenHwa,
Ding Shianling,
Wu PeiEi,
Shieh SheauYann,
Shen ChenYang
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.229
Subject(s) - biology , xrcc1 , dna damage , phosphorylation , base excision repair , dna repair , microbiology and biotechnology , dna , nucleotide excision repair , cancer research , genetics , gene , genotype , single nucleotide polymorphism
The DNA damage response (DDR) has an essential function in maintaining genomic stability. Ataxia telangiectasia‐mutated (ATM)‐checkpoint kinase 2 (Chk2) and ATM‐ and Rad3‐related (ATR)‐Chk1, triggered, respectively, by DNA double‐strand breaks and blocked replication forks, are two major DDRs processing structurally complicated DNA damage. In contrast, damage repaired by base excision repair (BER) is structurally simple, but whether, and how, the DDR is involved in repairing this damage is unclear. Here, we demonstrated that ATM‐Chk2 was activated in the early response to oxidative and alkylation damage, known to be repaired by BER. Furthermore, Chk2 formed a complex with XRCC1, the BER scaffold protein, and phosphorylated XRCC1 in vivo and in vitro at Thr 284 . A mutated XRCC1 lacking Thr 284 phosphorylation was linked to increased accumulation of unrepaired BER intermediate, reduced DNA repair capacity, and higher sensitivity to alkylation damage. In addition, a phosphorylation‐mimic form of XRCC1 showed increased interaction with glycosylases, but not other BER proteins. Our results are consistent with the phosphorylation of XRCC1 by ATM‐Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition/excision step to promote BER.