Chromosomal breakage syndromes and the BRCA1 genome surveillance complex

Chromosomal instability can occur when the DNA damage response and repair p rocess fails, resulting in syndromes characterized by growth abnormalities, hematopoietic defects, mutagen sensitivity, and cancer predisposition. Mut ations in ATM, NBS1, MRE11, BLM, WRN, and FANCD2 are responsible for ataxia telangiectasia (AT), Nijmegen breakage syndrome, AT-like disorder, Bloom a nd Werner syndrome, and Fanconi anemia group D2, respectively. This diverse group of disorders is thought to be linked through protein interactions wi th the breast cancer tumor susceptibility gene product, BRCA1. BRCA1 forms a multi-subunit protein complex referred to as the BRCA1-associated genome surveillance complex (BASC), which includes DNA damage repair proteins such as MSH2-MSH6 and MLH1, as well as ATM, NBS1, MRE11, and BLM. Although stil l controversial, this finding suggests similarities in the pathogenesis of the human chromosome breakage syndromes and a complementary role for each p rotein in DNA structure surveillance or damage repair.