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 harb...

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Published inGenes & development Vol. 14; no. 11; pp. 1400 - 1406
Main Authors Yu, V P, Koehler, M, Steinlein, C, Schmid, M, Hanakahi, L A, van Gool, A J, West, S C, Venkitaraman, A R
Format Journal Article
LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 01.06.2000
Subjects
Animals
Annexin A5 - metabolism
BRCA2 gene
BRCA2 Protein
Cells, Cultured
Chromosome Aberrations
Chromosomes - genetics
Cross-Linking Reagents - pharmacology
DNA Damage
DNA Repair - genetics
DNA-Binding Proteins - genetics
Flow Cytometry
Gene Silencing
Genetic Predisposition to Disease
In Situ Nick-End Labeling
Karyotyping
Liver - embryology
Mice
Mitomycin - pharmacology
Mutagenesis
Neoplasm Proteins - genetics
Rad51 Recombinase
Recombination, Genetic
Research Paper
Transcription Factors - genetics
Translocation, Genetic
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Summary: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.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
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Present address: N.V. Organon, Target Discovery Unit, Oss, The Netherlands.
Corresponding author.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.14.11.1400