Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia.

TitleDeficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia.
Publication TypeJournal Article
Year of Publication2015
AuthorsRickman KA, Lach FP, Abhyankar A, Donovan FX, Sanborn EM, Kennedy JA, Sougnez C, Gabriel SB, Elemento O, Chandrasekharappa SC, Schindler D, Auerbach AD, Smogorzewska A
JournalCell Rep
Volume12
Issue1
Pagination35-41
Date Published2015 Jul 07
ISSN2211-1247
KeywordsFanconi Anemia, Fanconi Anemia Complementation Group D2 Protein, Fanconi Anemia Complementation Group L Protein, Fibroblasts, Gene Deletion, HEK293 Cells, Humans, Protein Binding, Ubiquitin-Conjugating Enzymes, Ubiquitination
Abstract

Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT.

DOI10.1016/j.celrep.2015.06.014
Alternate JournalCell Rep
PubMed ID26119737
PubMed Central IDPMC4497947
Grant ListUL1 TR000043 / TR / NCATS NIH HHS / United States
R01 HL120922 / HL / NHLBI NIH HHS / United States
T32GM007739 / GM / NIGMS NIH HHS / United States
/ / Intramural NIH HHS / United States
8 UL1 TR000043 / TR / NCATS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States