The Fanconi Anaemia Components UBE2T and FANCM Are Functionally Linked to Nucleotide Excision Repair

Abstract

The many proteins that function in the Fanconi anaemia (FA) monoubiquitylation pathway initiate replicative DNA crosslink repair. However, it is not clear whether individual FA genes participate in DNA repair pathways other than homologous recombination and translesion bypass. Here we show that avian DT40 cell knockouts of two integral FA genes – UBE2T and FANCM are unexpectedly sensitive to UV-induced DNA damage. Comprehensive genetic dissection experiments indicate that both of these FA genes collaborate to promote nucleotide excision repair rather than translesion bypass to protect cells form UV genotoxicity. Furthermore, UBE2T deficiency impacts on the efficient removal of the UV-induced photolesion cyclobutane pyrimidine dimer. Therefore, this work reveals that the FA pathway shares two components with nucleotide excision repair, intimating not only crosstalk between the two major repair pathways, but also potentially identifying a UBE2T-mediated ubiquitin-signalling response pathway that contributes to nucleotide excision repair.

Functions and regulation of the multitasking FANCM family of DNA motor proteins

“…Likewise, the manner in which Mph1 functions with Fkh1, Msh2-Msh6, and Mgm101 in ICL repair or with Elg1 possibly in lagging strand DNA synthesis remains to be delineated (Ho et al 2002;Gavin et al 2006;Kang et al 2012;Ward et al 2012;Singh et al 2013a). In addition, recent studies suggest that FANCM family proteins function in additional processes; e.g., in nucleotide excision repair to remove bulky DNA adducts induced by ultraviolet light treatment (Kelsall et al 2012). Finally, even though FANCM phosphorylation is clearly important for its cellular functions, there is a paucity of information regarding how the biochemical attributes of FANCM family proteins are influenced by phosphorylation and other posttranslational modifications.…”

Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3

“…However, there is some evidence that UBE2T might be associated with ubiquitin signalling pathways other than FA. In contrast with FA core complex-deficient cells (including FANCL deficiency), UBE2T deletion in the avian cell line DT40 (a lymphoblastoid cell) caused hypersensitivity to UV light and cells are less efficient in removing genotoxic cyclobutane pyrimidine photoadducts [117]. Further somatic genetic analysis revealed a genetic link between UBE2T and the nucleotide excision repair gene XPA, suggesting an UBE2T-mediated signalling pathway required for efficient nucleotide excision repair of certain UV lesions.…”

Structure analysis of FAAP24 reveals single-stranded DNA-binding activity and domain functions in DNA damage response

“…XPF mutations can cause xeroderma pigmentosum, a genetic disease that is highly prone to skin cancer. Fanconi anemia (FA), complementation group M (FANCM) and FAassociated protein, 24-KD (FAAP24) belong to the XPF family of proteins and are implicated in the repair of UV and interstrand crosslink (ICL) damage [1,3]. FANCM mutation has been found in the rare genetic disorder FA [4].…”