title: In vitro analysis of genomic instability triggered by BRCA1 missense mutations.
abstract: 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.
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università degli Studi di Catanzaro Magna Graecia, Viale Europa Campus Germaneto, 88100 Catanzaro, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Quaresima
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Faniello
authors.forename: Francesco
authors.initials: F
authors.lastname: Baudi
authors.forename: Telma
authors.initials: T
authors.lastname: Crugliano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cuda
authors.forename: Francesco
authors.initials: F
authors.lastname: Costanzo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Venuta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology; D019398:Genes, BRCA1; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D018895:Microsatellite Repeats; D008957:Models, Genetic; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1