HERC2 is an E3 ligase that targets BRCA1 for degradation.
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.
Wu
Wenwen
W
Division of Breast and Endocrine Surgery, Department of Surgery, St. Marianna University School of Medicine, Kawasaki, Japan.
Sato
Ko
K
Koike
Ayaka
A
Nishikawa
Hiroyuki
H
Koizumi
Hirotaka
H
Venkitaraman
Ashok R
AR
Ohta
Tomohiko
T
D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D016195:G2 Phase / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D016196:S Phase / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases