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Molecular and Cellular Biology, August 2004, p. 6701-6709, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6701-6709.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

BRCA1 Is Required for Common-Fragile-Site Stability via Its G2/M Checkpoint Function

Martin F. Arlt,1 Bo Xu,2 Sandra G. Durkin,1 Anne M. Casper,1 Michael B. Kastan,3 and Thomas W. Glover1*

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109,1 Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70112,2 Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 381053

Received 9 January 2004/ Returned for modification 4 March 2004/ Accepted 4 May 2004

Common fragile sites are loci that form chromosome gaps or breaks when DNA synthesis is partially inhibited. Fragile sites are prone to deletions, translocations, and other rearrangements that can cause the inactivation of associated tumor suppressor genes in cancer cells. It was previously shown that ATR is critical to fragile-site stability and that ATR-deficient cells have greatly elevated fragile-site expression (A. M. Casper, P. Nghiem, M. F. Arlt, and T. W. Glover, Cell 111:779-789, 2002). Here we demonstrate that mouse and human cells deficient for BRCA1, due to mutation or knockdown by RNA interference, also have elevated fragile-site expression. We further show that BRCA1 functions in the induction of the G2/M checkpoint after aphidicolin-induced replication stalling and that this checkpoint function is involved in fragile-site stability. These data indicate that BRCA1 is important in fragile-site stability and that fragile sites are recognized by the G2/M checkpoint pathway, in which BRCA1 plays a key role. Furthermore, they suggest that mutations in BRCA1 or interacting proteins could lead to rearrangements at fragile sites in cancer cells.

* Corresponding author. Mailing address: Department of Human Genetics, 4909 Buhl, Box 0618, 1241 E. Catherine St., University of Michigan, Ann Arbor, MI 48109-0618. Phone: (734) 763-5222. Fax: (734) 763-3784. E-mail: glover{at}umich.edu.

Molecular and Cellular Biology, August 2004, p. 6701-6709, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6701-6709.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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