title: Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia.
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.
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Rickman
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Francis P
authors.initials: FP
authors.lastname: Lach
authors.affiliation: New York Genome Center, New York, NY 10013, USA.
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Frank X
authors.initials: FX
authors.lastname: Donovan
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Sanborn
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kennedy
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Settara C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.affiliation: Institute for Human Genetics, Biozentrum, Universität Würzburg, 97074 Würzburg, Germany.
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.affiliation: Human Genetics and Hematology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Arleen D
authors.initials: AD
authors.lastname: Auerbach
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA. Electronic address: asmogorzewska@rockefeller.edu.
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
mesh_terms: D005199:Fanconi Anemia / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D052240:Fanconi Anemia Complementation Group L Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D044763:Ubiquitin-Conjugating Enzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C513404:UBE2T protein, human; D044763:Ubiquitin-Conjugating Enzymes; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein