HERC2 Is an E3 Ligase That Targets BRCA1 for Degradation

Cancer Res; 70(15); 6384–92. ©2010 AACR.The breast cancer suppressor BRCA1 forms a stable heterodimeric E3 ubiquitin ligase with BARD1. Eachprotein controls the abundance and stability of the other, and loss of the interaction leads to BRCA1 degradation.Here, we show that HERC2, a protein recently implicated in DNA damage repair, targets BARD1-uncoupled BRCA1 for degradation. HERC2 shuttles between the nucleus and the cytoplasm. Its COOH-terminalHECT-containing domain interacts with an NH2-terminal degron domain in BRCA1. HERC2 ubiquitinatesBRCA1; this reaction depends on Cys4762 of HERC2, the catalytic ubiquitin binding site, and the degron ofBRCA1. The HERC2-BRCA1 interaction is maximal during the S phase of the cell cycle and rapidly diminishesas cells enter G2-M, inversely correlated with the steady-state level of BRCA1. Significantly, HERC2 depletionantagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G2-M checkpoint activity. Conversely,BARD1 protects BRCA1 from HERC2-mediated ubiquitination. Collectively, our findings identify afunction for HERC2 in regulating BRCA1 stability in opposition to BARD1. The HERC2 expression in breastepithelial cells and breast carcinomas suggests that this mechanism may play a role in breast carcinogenesis.Cancer Res; 70(15); 6384–92. ©2010 AACR.