HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway.
The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn-proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1 binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half-life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin-proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1-mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis.
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China; Institute of Systems Biology, Peking University, Beijing 100191, China.
Xiaozhen
X
Wang
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Guang
G
Lu
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Li
L
Li
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Juan
J
Yi
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Kaowen
K
Yan
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Yaqing
Y
Wang
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Baili
B
Zhu
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Jingyu
J
Kuang
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Ming
M
Lin
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
Sha
S
Zhang
Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China; Institute of Systems Biology, Peking University, Beijing 100191, China. Electronic address: gzshao@bjmu.edu.cn.
Genze
G
Shao
D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D060066:Protein Interaction Maps; D055550:Protein Stability; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D019313:BRCA1 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
BRCA1; Degradation; HUWE1; Ubiquitination