title: UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2.
abstract: Fanconi anemia (FA) is a rare cancer-predisposing genetic disease mostly caused by improper regulation of the monoubiquitination of Fanconi anemia complementation group D2 (FANCD2). Genetic studies have indicated that ubiquitin conjugating enzyme UBE2T and HHR6 could regulate FANCD2 monoubiquitination through distinct mechanisms. However, the exact regulation mechanisms of FANCD2 monoubiquitination in response to different DNA damages remain unclear. Here we report that UBE2W, a new ubiquitin conjugating enzyme, could regulate FANCD2 monoubiquitination by mechanisms different from UBE2T or HHR6. Indeed, UBE2W exhibits ubiquitin conjugating enzyme activity and catalyzes the monoubiquitination of PHD domain of Fanconi anemia complementation group L (FANCL) in vitro. UBE2W binds to FANCL, and the PHD domain is both necessary and sufficient for this interaction in mammalian cells. In addition, over-expression of UBE2W in cells promotes the monoubiquitination of FANCD2 and down-regulated UBE2W markedly reduces the UV irradiation-induced but not MMC-induced FANCD2 monoubiquitination. These results indicate that UBE2W regulates FANCD2 monoubiquitination by mechanisms different from UBE2T and HRR6. It may provide an additional regulatory step in the activation of the FA pathway.
authors.affiliation: Laboratory of Protein Engineering, Institute of Biotechnology, Beijing, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhou
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhao
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Hengqi
authors.initials: H
authors.lastname: Zhu
authors.forename: Long
authors.initials: L
authors.lastname: Xu
authors.forename: Liran
authors.initials: L
authors.lastname: Shan
authors.forename: Xiang
authors.initials: X
authors.lastname: Liao
authors.forename: Zekun
authors.initials: Z
authors.lastname: Guo
authors.forename: Peitang
authors.initials: P
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D052240:Fanconi Anemia Complementation Group L Protein / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000187:drug effects / Q000528:radiation effects; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D016685:Mitomycin; C510626:UBE2W protein, human; C558780:UBE2W protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D052240:Fanconi Anemia Complementation Group L Protein