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.
HERC2 is an E3 ligase that targets BRCA1 for degradation.
Wenwen Wu,Ko Sato,Ayaka Koike,Hiroyuki Nishikawa,H. Koizumi,A. Venkitaraman,T. Ohta
Published 2010 in Cancer Research
ABSTRACT
PUBLICATION RECORD
- Publication year
2010
- Venue
Cancer Research
- Publication date
2010-08-01
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- bard1
A BRCA1-binding partner that forms a stable heterodimeric E3 ubiquitin ligase with BRCA1.
- brca1
A breast cancer suppressor protein that forms a heterodimeric E3 ligase complex with BARD1.
- g2-m checkpoint activity
The checkpoint function that restrains progression into mitosis during the G2-to-M transition.
Aliases: G(2)-M checkpoint activity
- herc2
A HECT-domain-containing ubiquitin ligase that shuttles between the nucleus and the cytoplasm.
- herc2-brca1 interaction
The physical association between HERC2 and BRCA1, mediated here by HERC2's COOH-terminal HECT-containing domain and the BRCA1 NH2-terminal degron domain.
Aliases: HERC2-BRCA1 binding
- ubiquitination
A post-translational modification in which ubiquitin is attached to a substrate protein.
REFERENCES
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