Abstract
The breast cancer suppressor BRCA1 forms a stable heterodimeric E3 ubiquitin ligase with BARD1. Each protein 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-terminal HECT-containing domain interacts with an NH(2)-terminal degron domain in BRCA1. HERC2 ubiquitinates BRCA1; this reaction depends on Cys(4762) of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1. The HERC2-BRCA1 interaction is maximal during the S phase of the cell cycle and rapidly diminishes as cells enter G(2)-M, inversely correlated with the steady-state level of BRCA1. Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G(2)-M checkpoint activity. Conversely, BARD1 protects BRCA1 from HERC2-mediated ubiquitination. Collectively, our findings identify a function for HERC2 in regulating BRCA1 stability in opposition to BARD1. The HERC2 expression in breast epithelial cells and breast carcinomas suggests that this mechanism may play a role in breast carcinogenesis.
Highlights
The BRCA1 tumor suppressor is a key player in breast and ovarian carcinogenesis
We show that HERC2 is an E3 ligase that targets BRCA1 for degradation during the S phase of cell www.aacrjournals.org cycle
It has been reported that BRCA1 protein expression becomes maximal at late S and G2-M phases [4,5,6,7,8]
Summary
The BRCA1 tumor suppressor is a key player in breast and ovarian carcinogenesis. BRCA1 maintains genomic stability by functioning in DNA damage repair, cell cycle checkpoint activity, and apoptosis [3]. One significant property of BRCA1 is that it is a cell cycle–regulated protein. Its expression level and phosphorylation status oscillate during the cell cycle [4,5,6,7,8]. The expression level is regulated by both transcription and protein stability. It has been shown that BRCA1 turnover increases in S phase by ubiquitin-dependent proteolysis [7], features that regulate BRCA1 protein stability are largely unknown. One significant factor that regulates the stability of BRCA1 is the protein BARD1.
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