BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP.
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.
Yu
Xiaochun
X
Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Fu
Shuang
S
Lai
Maoyi
M
Baer
Richard
R
Chen
Junjie
J
D019313:BRCA1 Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002384:Catalysis; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004706:Endodeoxyribonucleases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D019313:BRCA1 Protein; D002352:Carrier Proteins; D002843:Chromatin; D009687:Nuclear Proteins; D012694:Serine; D044767:Ubiquitin-Protein Ligases; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; D046988:Proteasome Endopeptidase Complex