BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function.

Journal Article (Journal Article)

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 G(2)/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 G(2)/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.

Full Text

Duke Authors

Cited Authors

  • Arlt, MF; Xu, B; Durkin, SG; Casper, AM; Kastan, MB; Glover, TW

Published Date

  • August 2004

Published In

Volume / Issue

  • 24 / 15

Start / End Page

  • 6701 - 6709

PubMed ID

  • 15254237

Pubmed Central ID

  • PMC444841

International Standard Serial Number (ISSN)

  • 0270-7306

Digital Object Identifier (DOI)

  • 10.1128/MCB.24.15.6701-6709.2004


  • eng

Conference Location

  • United States