Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation.

摘要: 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, sequence with similarity damaged chromosome directs the damage. The protein products hereditary breast cancer susceptibility genes, BRCA1 BRCA2, interact Rad51 protein, central component pathways. We have recently shown that interaction significant by demonstrating Brca1- BRCA2-deficient cells are defective homology-directed repair. confirm Brca1-deficient embryonic stem (ES) gene targeting an I-Sce I-induced break. phenotypic paradigm defines mutants extended these demonstration 100-fold sensitivity interstrand cross-linking agent mitomycin-C spontaneous instability. Interestingly, although aberrations were evident, aneuploidy was not observed. Repair phenotypes partially restored expression Brca1 transgene, whereas correction one mutated allele through fully restores resistance stability. conclude inability properly strand gives rise defects maintenance promote genetic instability and, it likely, tumorigenesis.