DOG-1 is the Caenorhabditis elegans BRIP1/FANCJ homologue and functions in interstrand cross-link repair.
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.
Youds
Jillian L
JL
DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, United Kingdom.
Barber
Louise J
LJ
Ward
Jordan D
JD
Collis
Spencer J
SJ
O'Neil
Nigel J
NJ
Boulton
Simon J
SJ
Rose
Ann M
AM
D000595:Amino Acid Sequence; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009154:Mutation; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D029742:Caenorhabditis elegans Proteins; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D004265:DNA Helicases; C464789:Dog-1 protein, C elegans; C000618935:BRIP1 protein, human; D020365:RNA Helicases