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Molecular and Cellular Biology, March 2008, p. 1470-1479, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01641-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Jillian L. Youds,1 Louise J. Barber,2 Jordan D. Ward,2 Spencer J. Collis,2 Nigel J. O'Neil,1 Simon J. Boulton,2* and Ann M. Rose1

Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 2G9, Canada,1 DNA Damage Response Laboratory, Cancer Research UK, The London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, United Kingdom2

Received 5 September 2007/ Returned for modification 5 October 2007/ Accepted 11 December 2007

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.

* Corresponding author. Mailing address: DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, United Kingdom. Phone: 44 (0)1707 62 5774. Fax: 44 (0)2072 69 3801. E-mail: simon.boulton{at}cancer.org.uk

{triangledown} Published ahead of print on 17 December 2007.

Molecular and Cellular Biology, March 2008, p. 1470-1479, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01641-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • London, T. B. C., Barber, L. J., Mosedale, G., Kelly, G. P., Balasubramanian, S., Hickson, I. D., Boulton, S. J., Hiom, K. (2008). FANCJ Is a Structure-specific DNA Helicase Associated with the Maintenance of Genomic G/C Tracts. J. Biol. Chem. 283: 36132-36139 [Abstract] [Full Text]  
  • Wu, Y., Shin-ya, K., Brosh, R. M. Jr. (2008). FANCJ Helicase Defective in Fanconia Anemia and Breast Cancer Unwinds G-Quadruplex DNA To Defend Genomic Stability. Mol. Cell. Biol. 28: 4116-4128 [Abstract] [Full Text]  


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