Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation.
Cancer-causing mutations often arise from gross chromosomal rearrangements (GCRs) such as translocations, which involve genetic exchange between nonhomologous chromosomes. Here we show that murine Brca2 has an essential function in suppressing GCR formation after chromosome breakage. Cells that harbor truncated Brca2 spontaneously incur GCRs and genomic DNA breaks during division. They exhibit hypersensitivity to DNA damage by interstrand cross-linkers, which even at low doses trigger aberrant genetic exchange between nonhomologous chromosomes. Therefore, genetic instability in Brca2-deficient cells results from the mutagenic processing of spontaneous or induced DNA damage into gross chromosomal rearrangements, providing a mechanistic basis for cancer predisposition.
Yu
V P
VP
University of Cambridge, CRC Department of Oncology and The Wellcome Trust Centre for Molecular Mechanisms in Disease, The Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK.
Koehler
M
M
Steinlein
C
C
Schmid
M
M
Hanakahi
L A
LA
van Gool
A J
AJ
West
S C
SC
Venkitaraman
A R
AR
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D024682:BRCA2 Protein; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000235:genetics*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D020287:In Situ Nick-End Labeling; D007621:Karyotyping; D008099:Liver / Q000196:embryology; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D016296:Mutagenesis; D009363:Neoplasm Proteins / Q000235:genetics*; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D017304:Annexin A5; D024682:BRCA2 Protein; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016685:Mitomycin; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse