Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation Journal Article


Authors: Moynahan, M. E.; Cui, T. Y.; Jasin, M.
Article Title: Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation
Abstract: Chromosomal breaks occur spontaneously as a result of normal DNA metabolism and after exposure to DNA-damaging agents. A major pathway involved in chromosomal double-strand break repair is homologous recombination. In this pathway, a DNA sequence with similarity to a damaged chromosome directs the repair of the damage. The protein products of the hereditary breast cancer susceptibility genes, BRCA1 and BRCA2, interact with the Rad51 protein, a central component of homologous repair pathways. We have recently shown that this interaction is significant by demonstrating that Brca1- and BRCA2-deficient cells are defective in homology-directed chromosomal break repair. We confirm that Brca1-deficient embryonic stem (ES) cells are defective in gene targeting and homology-directed repair of an I-Sce I-induced chromosome break. The phenotypic paradigm that defines homology-directed repair mutants is extended to these Brca1-deficient cells by the demonstration of 100-fold sensitivity to the interstrand cross-linking agent mitomycin-C and spontaneous chromosome instability. Interestingly, although chromosome aberrations were evident, aneupioldy was not observed. Repair phenotypes are partially restored by expression of a Brca1 transgene, whereas correction of one mutated Brca1 allele through gene targeting fully restores mitomycin-C resistance and chromosome stability. We conclude that the inability to properly repair strand breaks by homology-directed repair gives rise to defects in chromosome maintenance that promote genetic instability and, it is likely, tumorigenesis.
Keywords: controlled study; gene mutation; human cell; mutation; chromosome structure; phenotype; animals; mice; dna damage; gene targeting; dna repair; cancer susceptibility; breast cancer; gene expression; cell line; gene product; protein interaction; drug resistance, neoplasm; transfection; brca1 protein; brca2 protein; cancer inhibition; chromosome aberration; genetic transfection; genes, brca1; stem cells; mitomycin c; chromosome breakage; genetic stability; dna sequence; dna metabolism; sequence homology; mitomycin; transgenes; rad51 protein; genetic complementation test; molecular stability; cross-linking reagents; human; priority journal; article
Journal Title: Cancer Research
Volume: 61
Issue: 12
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2001-06-15
Start Page: 4842
End Page: 4850
Language: English
PUBMED: 11406561
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 21 May 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Mary Ellen Moynahan
    105 Moynahan
  2. Maria Jasin
    251 Jasin