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Molecular and Cellular Biology, January 2006, p. 425-437, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.425-437.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Fanconi Anemia Proteins Are Required To Prevent Accumulation of Replication-Associated DNA Double-Strand Breaks{dagger}

Alexandra Sobeck,1,{ddagger} Stacie Stone,1,{ddagger} Vincenzo Costanzo,7 Bendert de Graaf,1 Tanja Reuter,1 Johan de Winter,5 Michael Wallisch,1 Yassmine Akkari,2 Susan Olson,2 Weidong Wang,6 Hans Joenje,5 Jan L. Christian,3 Patrick J. Lupardus,8 Karlene A. Cimprich,8 Jean Gautier,4 and Maureen E. Hoatlin1*

Division of Biochemistry and Molecular Biology,1 Department of Molecular and Medical Genetics,2 Department of Cell and Developmental Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, Oregon 97239,3 Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, New York 10032,4 Department of Clinical Genetics and Human Genetics, Free University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands,5 National Institute on Aging, National Institutes of Health, 333 Cassell Dr., TRIAD Center Room 3000, Baltimore, Maryland 21224,6 Genome Stability Unit, Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, United Kingdom,7 Department of Molecular Pharmacology, Stanford University, Stanford, California 943058

Received 16 June 2005/ Returned for modification 20 July 2005/ Accepted 13 October 2005

Fanconi anemia (FA) is a multigene cancer susceptibility disorder characterized by cellular hypersensitivity to DNA interstrand cross-linking agents such as mitomycin C (MMC). FA proteins are suspected to function at the interface between cell cycle checkpoints, DNA repair, and DNA replication. Using replicating extracts from Xenopus eggs, we developed cell-free assays for FA proteins (xFA). Recruitment of the xFA core complex and xFANCD2 to chromatin is strictly dependent on replication initiation, even in the presence of MMC indicating specific recruitment to DNA lesions encountered by the replication machinery. The increase in xFA chromatin binding following treatment with MMC is part of a caffeine-sensitive S-phase checkpoint that is controlled by xATR. Recruitment of xFANCD2, but not xFANCA, is dependent on the xATR-xATR-interacting protein (xATRIP) complex. Immunodepletion of either xFANCA or xFANCD2 from egg extracts results in accumulation of chromosomal DNA breaks during replicative synthesis. Our results suggest coordinated chromatin recruitment of xFA proteins in response to replication-associated DNA lesions and indicate that xFA proteins function to prevent the accumulation of DNA breaks that arise during unperturbed replication.

* Corresponding author. Mailing address: Division of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Phone: (503) 494-1123. Fax: (503) 494-7368. E-mail:hoatlinm{at}ohsu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, January 2006, p. 425-437, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.425-437.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • 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]  
  • Kim, J. M., Kee, Y., Gurtan, A., D'Andrea, A. D. (2008). Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. Blood 111: 5215-5222 [Abstract] [Full Text]  
  • Stone, S., Sobeck, A., van Kogelenberg, M., de Graaf, B., Joenje, H., Christian, J., Hoatlin, M. E. (2007). Identification, developmental expression and regulation of the Xenopus ortholog of human FANCG/XRCC9. GENES CELLS 12: 841-851 [Abstract] [Full Text]  
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