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अमूर्त

Impaired Effects of a FANCC Splicing Isoform in FANC-BRCA DNA Repair Pathway

Bélanger S, Plourde KV, Beauparlant CJ, St-Laurent Pedneault C, Bouffard F, Ouellette G, Labrie Y1 and Durocher F

The integrity of the FANC gene family is essential for the proper reparation of DNA damages. Recently, different FANCC splice variants were identified. We characterized sequence variations and studied the impact of the alternative splicing event FANCC∆7 on DNA repair. The FANCC∆7 transcript is present in all breast cancer lines analyzed. Genomic and complementary DNA sequencing of non-BRCA1/2 individuals was performed to identify sequence variants and alternative transcripts of the FANCC gene. Ribosomal fractions allowed confirming the translation of FANCC∆7 into a functional protein. The variant protein seems to be secluded in the cytoplasm in transfected HEK293T cells following MMC treatments contrary to the FANCC protein that migrates to the nucleus. Performing localization studies, we observed evidences of colocalization of FANCC and FANCC∆7 with BRCA1 in centrosomes of cells. We demonstrated that FANCC deficient cells infected with FANCC∆7 cDNA show a blocking in G2/M in the presence of MMC. Finally, FANCC∆7 is unable to allow the monoubiquitination of FANCD2. This study unravels the incapability of the FANCC∆7 splicing event to permit the reparation of interstrand crosslinks induced by MMC. This work unravels a novel layer of complexity to the understanding of the fascinating FANC-BRCA DNA repair pathway.