Human Molecular Genetics

Human Molecular Genetics Advance Access originally published online on April 28, 2004

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Human Molecular Genetics, 2004, Vol. 13, No. 12 1241-1248
DOI: 10.1093/hmg/ddh135
Human Molecular Genetics, Vol. 13, No. 12 © Oxford University Press 2004; all rights reserved

Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways

Shobbir Hussain¹, James B. Wilson², Annette L. Medhurst³, James Hejna⁴, Emily Witt⁵, Sahana Ananth², Adelina Davies⁶, Jean-Yves Masson⁷, Robb Moses⁴, Stephen C. West⁶, Johan P. de Winter³, Alan Ashworth⁵, Nigel J. Jones² and Christopher G. Mathew^1,*

¹Division of Genetics and Development, Guy's, King's and St Thomas's School of Medicine, King's College London, London, UK, ²School of Biological Sciences, University of Liverpool, Liverpool, UK, ³Department of Clinical Genetics and Human Genetics, Free University Medical Centre, Amsterdam, The Netherlands, ⁴Oregon Health Sciences University, Portland, OR, USA, ⁵The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK, ⁶Cancer Research UK London Research Institute, Clare Hall Laboratories, Hertfordshire, UK and ⁷Laval University Cancer Research Center, Quebec City, Quebec, Canada

Received February 6, 2004; Revised April 5, 2004; Accepted April 19, 2004

Fanconi anaemia (FA) is a chromosomal instability disorder characterized by cellular sensitivity to DNA interstrand crosslinking agents and a high risk of cancer. Six of the eight proteins encoded by the known FA genes form a nuclear complex which is required for the monoubiquitination of the FANCD2 protein. FANCD2 complexes and colocalizes with BRCA1, but its presumptive role in DNA repair has not yet been clearly defined. We used yeast two-hybrid analysis to test for interaction between FANCD2 and 10 proteins involved in homologous recombination repair. FANCD2 did not interact with RAD51, the five RAD51 paralogs, RAD52, RAD54 or DMC1. However, it bound to a highly conserved C-terminal site in BRCA2 that also binds FANCG/XRCC9. FANCD2 and BRCA2 can be coimmunoprecipitated from cell extracts of both human and Chinese hamster wild-type cells, thus confirming that the interaction occurs in vivo. Formation of nuclear foci of FANCD2 was normal in the BRCA2 mutant CAPAN-1 cells, which indicates that the recruitment of FANCD2 to sites of DNA-repair is independent of wild-type BRCA2 function. FANCD2 colocalized with RAD51 in foci following treatment with mitomycin C or hydroxyurea, and colocalized very tightly with PCNA after treatment with hydroxyurea. These findings suggest that FANCD2 may have a role in the cellular response to stalled replication forks or in the repair of replication-associated double-strand breaks, irrespective of the type of primary DNA lesion.

^* To whom correspondence should be addressed at: Division of Genetics and Development GKT, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK. Tel: +44 2071883721; Fax: +44 2071882585; Email: christopher.mathew{at}genetics.kcl.ac.uk

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