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.

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…Recent studies indicate that ubiquitinlike with PHD and RING finger domain 1 (UHRF1) protein functions as an ICL recognition factor and may participate in these steps (Liang et al 2015. Recently, we and two different groups identified UBE2T, which encodes an E2 ubiquitin-conjugating enzyme, as a causative gene for FA (Hira et al 2015, Rickman et al 2015, Virts et al 2015. UBE2T/FANCT is essential for this monoubiquitination event to proceed.…”

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

“…Mutations in at least 19 FANC genes have been identified in patients with FA, while FANCD2/FANCI-associated nuclease 1 (FAN1) is the only known gene that is found to be inactivated in KIN patients (Zhou et al 2012;Rickman et al 2015;Wang and Smogorzewska 2015). Proteins encoded by the FANC genes (FANCA to FANCT) are directly involved in the repair of the ICL lesions during DNA replication (for review, see Kottemann and Smogorzewska 2013;Walden and Deans 2014;Wang and Smogorzewska 2015).…”

Genetic diagnosis of Fanconi anemia. Literature review

“…Взаимодействие с core complex [4] Примечание. MLPA -мультиплексная амплификация лигазносвязанных проб; ПЦР в РВ -полимеразная цепная реакция в режиме реального времени.…”

“…таб-лицу) [4,5]. Мутации в генах выявляют как в случаях с характерными аномалиями развития и симптомами костномозговой недостаточности, так и в случаях без анемии или каких-либо пороков развития.…”