DOG-1 Is the Caenorhabditis elegans BRIP1/FANCJ Homologue and Functions in Interstrand Cross-Link Repair

Abstract

Fanconi anemia (FA) is a cancer susceptibility syndrome characterized by defective DNA interstrand cross-link (ICL) repair. Here, we show that DOG-1 is the Caenorhabditis elegans homologue of FANCJ, a helicase mutated in FA-J patients. DOG-1 performs a conserved role in ICL repair, as dog-1 mutants are hypersensitive to ICL-inducing agents, but not to UVC irradiation or X rays. Genetic analysis indicated that dog-1 is epistatic with fcd-2 (C. elegans FANCD2) but is nonepistatic with brc-1 (C. elegans BRCA1), thus establishing the existence of two distinct pathways of ICL repair in worms. Furthermore, DOG-1 is dispensable for FCD-2 and RAD-51 focus formation, suggesting that DOG-1 operates downstream of FCD-2 and RAD-51 in ICL repair. DOG-1 was previously implicated in poly(G)/poly(C) (G/C) tract maintenance during DNA replication. G/C tracts remain stable in the absence of ATL-1, CLK-2 (FA pathway activators), FCD-2, BRC-2, and MLH-1 (associated FA components), implying that DOG-1 is the sole FA component required for G/C tract maintenance in a wild-type background. However, FCD-2 is required to promote deletion-free repair at G/C tracts in dog-1 mutants, consistent with a role for FA factors at the replication fork. The functional conservation between DOG-1 and FANCJ suggests a possible role for FANCJ in G/C tract maintenance in human cells.

ACKNOWLEDGMENTS

We thank S. Mitani and the International C. elegans Knockout Consortium for generating strains. Some strains were provided by the Caenorhabditis elegans Genetics Centre, which is supported by the National Institutes of Health Center for Research Resources. Don Riddle, Don Moerman, and David Baillie are acknowledged for sharing laboratory equipment.

This work was supported by a Natural Sciences and Engineering Research Council (NSERC) discovery grant and a Canadian Institutes of Health Research grant (A.M.R.), as well as an NSERC scholarship and Michael Smith Foundation for Health Research fellowship (J.L.Y.). Funds for this project were also provided by Cancer Research UK (S.J.B.) and the Fanconi Anemia Research Fund (S.J.C. and S.J.B.).