title: HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway.
abstract: 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. HUWE1binds 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.
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China; Institute of Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yi
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Kaowen
authors.initials: K
authors.lastname: Yan
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Baili
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Kuang
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Cell Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Genze
authors.initials: G
authors.lastname: Shao
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: BRCA1; Degradation; HUWE1; Ubiquitination