Journal
CELL RESEARCH
Volume 22, Issue 2, Pages 305-320Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2011.128
Keywords
DNA damage signaling; arginine methylation; GAR motif; MRE11; ATR
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Funding
- Canadian Institutes of Health Research [MOP-67070]
- Cancer Research Network of Fonds de la Recherche en Sante du Quebec
- NIH [R01 HL079118]
- Leukemia and Lymphoma Society
- CIHR [MOP-102722]
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The MRE11/RAD50/NBS1 complex is the primary sensor rapidly recruited to DNA double-strand breaks (DSBs). MRE11 is known to be arginine methylated by PRMT1 within its glycine-arginine-rich (GAR) motif. In this study, we report a mouse knock-in allele of Mre11 that substitutes the arginines with lysines in the GAR motif and generates the MRE11(RK) protein devoid of methylated arginines. The Mre11(RK/RK) mice were hypersensitive to.-irradiation (IR) and the cells from these mice displayed cell cycle checkpoint defects and chromosome instability. Moreover, the Mre11(RK/RK) MEFs exhibited ATR/CHK1 signaling defects and impairment in the recruitment of RPA and RAD51 to the damaged sites. The (MRN)-R-RK complex formed and localized to the sites of DNA damage and normally activated the ATM pathway in response to IR. The (MRN)-R-RK complex exhibited exonuclease and DNA-binding defects in vitro responsible for the impaired DNA end resection and ATR activation observed in vivo in response to IR. Our findings provide genetic evidence for the critical role of the MRE11 GAR motif in DSB repair, and demonstrate a mechanistic link between post-translational modifications at the MRE11 GAR motif and DSB processing, as well as the ATR/CHK1 checkpoint signaling.
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