Journal
HUMAN MUTATION
Volume 27, Issue 7, Pages 715-U13Publisher
WILEY
DOI: 10.1002/humu.9427
Keywords
BRCA1; BRCT; MLH1; MSI; breast cancer
Categories
Funding
- MIUR (Ministero Universita e Ricerca Scientifica e Tecnologica) from Ministero della Salute, Ricerca Finalizzata [COFIN 2003, COFIN 2004, CLUSTER C-04]
- MIUR (Ministero Universita e Ricerca Scientifica e Tecnologica) from AIRC (Associazione Italiana Ricerca sul Cancro)
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The BRCA1 tumor suppressor gene encodes a phosphoprotein involved in many cellular key functions including DNA repair, transcription regulation, cell-cycle control and apoptosis. Most of these functions are strictly related to the ability of BRCA1 to interact with the other partners of a multimeric complex called BASC. Among these components, an important role is played by the human homolog of the bacterial MutL, MLH1. In this study, we have identified the BRCA1 binding domains to MLH1 and demonstrated that three distinct mutations in one of these interaction domains can produce, in vitro, a microsatellite instability phenotype, one of the hallmarks of an imbalance in the mismatch DNA repair machinery. These data support a model in which a structural modification in a critical domain of the BRCA1 gene product secondary to single amino acid mutations, may be able, per se, to impair the DNA damage response pathway, inducing genomic instability and eventually leading to breast carcinogenesis. (C) 2006 Wiley-Liss, Inc.
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