title: UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation.
abstract: The Fanconi anemia pathway is required for the efficient repair of damaged DNA. A key step in this pathway is the monoubiquitination of the FANCD2 protein by the ubiquitin ligase (E3) composed of Fanconi anemia core complex proteins. Here, we show that UBE2T is the ubiquitin-conjugating enzyme (E2) essential for this pathway. UBE2T binds to FANCL, the ubiquitin ligase subunit of the Fanconi anemia core complex, and is required for the monoubiquitination of FANCD2 in vivo. DNA damage in UBE2T-depleted cells leads to the formation of abnormal chromosomes that are a hallmark of Fanconi anemia. In addition, we show that UBE2T undergoes automonoubiquitination in vivo. This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T. Therefore, UBE2T is the E2 in the Fanconi anemia pathway and has a self-inactivation mechanism that could be important for negative regulation of the Fanconi anemia pathway.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Yuichi J
authors.initials: YJ
authors.lastname: Machida
authors.forename: Yuka
authors.initials: Y
authors.lastname: Machida
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Allan M
authors.initials: AM
authors.lastname: Gurtan
authors.forename: Gary M
authors.initials: GM
authors.lastname: Kupfer
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
mesh_terms: D002869:Chromosome Aberrations / Q000187:drug effects; D005199:Fanconi Anemia / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D052240:Fanconi Anemia Complementation Group L Protein / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D011485:Protein Binding; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D025801:Ubiquitin; D016685:Mitomycin; C513404:UBE2T protein, human; D044763:Ubiquitin-Conjugating Enzymes; D052240:Fanconi Anemia Complementation Group L Protein