BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function.
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.
Arlt
Martin F
MF
Department of Human Genetics, 4909 Buhl, Box 0618, 1241 E. Catherine Street, University of Michigan, Ann Arbor, MI 48109-0618, USA.
Xu
Bo
B
Durkin
Sandra G
SG
Casper
Anne M
AM
Kastan
Michael B
MB
Glover
Thomas W
TW
D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D004249:DNA Damage; D005434:Flow Cytometry; D016195:G2 Phase; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D011233:Precipitin Tests; D034622:RNA Interference; D014162:Transfection
D019313:BRCA1 Protein