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Molecular and Cellular Biology, May 2003, p. 3417-3426, Vol. 23, No. 10
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.10.3417-3426.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome

Amom Ruhikanta Meetei,1 Salvatore Sechi,2,{dagger} Michael Wallisch,3 Dafeng Yang,1 Mary K. Young,4 Hans Joenje,5 Maureen E. Hoatlin,3 and Weidong Wang1*

Laboratory of Genetics,1 Mass Spectrometry Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224,2 Division of Molecular Medicine, Oregon Health and Science University, Portland, Oregon 97201,3 Division of Immunology, Beckman Institute of the City of Hope, Duarte, California 91010,4 Department of Clinical Genetics and Human Genetics, Free University Medical Center, NL-1081 BT Amsterdam, The Netherlands5

Received 9 October 2002/ Returned for modification 10 December 2002/ Accepted 13 February 2003

Bloom syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one of the complexes, termed BRAFT, also contains five of the Fanconi anemia (FA) complementation group proteins (FA proteins). FA resembles BS in genomic instability and cancer predisposition, but most of its gene products have no known biochemical activity, and the molecular pathogenesis of the disease is poorly understood. BRAFT displays a DNA-unwinding activity, which requires the presence of BLM because complexes isolated from BLM-deficient cells lack such an activity. The complex also contains topoisomerase III{alpha} and replication protein A, proteins that are known to interact with BLM and could facilitate unwinding of DNA. We show that BLM complexes isolated from an FA cell line have a lower molecular mass. Our study provides the first biochemical characterization of a multiprotein FA complex and suggests a connection between the BLM and FA pathways of genomic maintenance. The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair.

* Corresponding author. Mailing address: Laboratory of Genetics, Mass Spectrometry Unit, National Institute on Aging, National Institutes of Health, 333 Cassell Dr., TRIAD Center Rm. 3000, Baltimore, MD 21224. Phone: (410) 558-8334. Fax: (410) 558-8331. E-mail: wangw{at}grc.nia.nih.gov.

{dagger} Present address: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892-5460.

Molecular and Cellular Biology, May 2003, p. 3417-3426, Vol. 23, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.10.3417-3426.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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