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In vitro analysis of genomic instability triggered by BRCA1 missense mutations

In vitro analysis of genomic instability triggered by BRCA1 missense mutations 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. © 2006 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Mutation Wiley

In vitro analysis of genomic instability triggered by BRCA1 missense mutations

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References (33)

Publisher
Wiley
Copyright
Copyright © 2006 Wiley Subscription Services, Inc., A Wiley Company
ISSN
1059-7794
eISSN
1098-1004
DOI
10.1002/humu.9427
pmid
16786532
Publisher site
See Article on Publisher Site

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. © 2006 Wiley‐Liss, Inc.

Journal

Human MutationWiley

Published: Jul 1, 2006

Keywords: BRCA1; BRCT; MLH1; MSI; breast cancer

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