The Carboxy Terminus of FANCE Recruits FANCD2 to the FA E3 Ligase Complex to Promote the Fanconi Anemia DNA Repair Pathway.

Fanconi Anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA crosslinking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multi-subunit E3 ubiquitin ligase complex, ...
or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. In order to delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C-terminus, referred to as F522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting Cisplatin resistance. Intriguingly, ectopic expression of the FANCE C-terminus fragment alone in FA-normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA crosslink repair.
J. Biol. Chem.
Date: Jan. 22, 2014
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