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RESEARCH COMMUNICATION
1 Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA; 2 Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, New York 10032, USA
BRCA1 (Breast Cancer Susceptibility Gene 1) possesses an N-terminal Ring domain and tandem C-terminal BRCT motifs. While the Ring domain has E3 ubiquitin ligase activity, the BRCA1 BRCT domains specifically recognize phospho-serine motifs. Here, we demonstrate that BRCA1 Ring domain catalyzes CtIP ubiquitination in a manner that depends on a phosphorylation-mediated interaction between CtIP and BRCA1 BRCT domains. The BRCA1-dependent ubiquitination of CtIP does not target CtIP for degradation. Instead, ubiquitinated CtIP associates with chromatin following DNA damage and participates in G2/M checkpoint control. Thus, we propose that BRCA1 can regulate the functions of its substrates through nonproteasomal pathways that do not involve substrate degradation.
[Keywords: BRCA1; CtIP; ubiquitination; DNA damage; phosphorylation; BRCT domain]
Received March 20, 2006; revised version accepted May 2, 2006.
E-MAIL chen.junjie{at}mayo.edu; FAX (507) 284-3906.
5 E-MAIL rb670{at}columbia.edu; FAX (212) 851-5267.
Supplemental material is available at http://www.genesdev.org.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1431006
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