Document Detail

ATM- and ATR-mediated phosphorylation of XRCC3 regulates DNA double-strand break-induced checkpoint activation and repair.
MedLine Citation:
PMID:  23438602     Owner:  NLM     Status:  MEDLINE    
The RAD51 paralogs XRCC3 and RAD51C have been implicated in homologous recombination (HR) and DNA damage responses. However, the molecular mechanism(s) by which these paralogs regulate HR and DNA damage signaling remains obscure. Here, we show that an SQ motif serine 225 in XRCC3 is phosphorylated by ATR kinase in an ATM signaling pathway. We find that RAD51C but not XRCC2 is essential for XRCC3 phosphorylation, and this modification follows end resection and is specific to S and G2 phases. XRCC3 phosphorylation is required for chromatin loading of RAD51 and HR-mediated repair of double-strand breaks (DSBs). Notably, in response to DSBs, XRCC3 participates in the intra-S-phase checkpoint following its phosphorylation and in the G2/M checkpoint independently of its phosphorylation. Strikingly, we find that XRCC3 distinctly regulates recovery of stalled and collapsed replication forks such that phosphorylation is required for the HR-mediated recovery of collapsed replication forks but is dispensable for the restart of stalled replication forks. Together, these findings suggest that XRCC3 is a new player in the ATM/ATR-induced DNA damage responses to control checkpoint and HR-mediated repair.
Kumar Somyajit; Shivakumar Basavaraju; Ralph Scully; Ganesh Nagaraju
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-02-25
Journal Detail:
Title:  Molecular and cellular biology     Volume:  33     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-08     Completed Date:  2013-05-29     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1830-44     Citation Subset:  IM    
Department of Biochemistry, Indian Institute of Science, Bangalore, India.
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MeSH Terms
Amino Acid Sequence
Cell Cycle Checkpoints*
Cell Cycle Proteins / metabolism*
Cell Line
DNA / chemistry,  genetics
DNA Breaks, Double-Stranded*
DNA Repair
DNA-Binding Proteins / chemistry,  metabolism*
Molecular Sequence Data
Protein-Serine-Threonine Kinases / metabolism*
Sequence Alignment
Tumor Suppressor Proteins / metabolism*
Grant Support
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/RAD51C protein, human; 0/Tumor Suppressor Proteins; 0/X-ray repair cross complementing protein 3; 0/XRCC2 protein, human; 9007-49-2/DNA; EC 2.7.1.-/ATR protein, human; EC Kinases; EC telangiectasia mutated protein

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