Cascades of genetic instability resulting from compromised break-induced replication

Break-induced replication (BIR) is a mechanism to repair double-strand breaks (DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities includ...

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Bibliographic Details
Published in:PLoS genetics 2014-02, Vol.10 (2), p.e1004119
Main Authors: Vasan, Soumini, Deem, Angela, Ramakrishnan, Sreejith, Argueso, Juan Lucas, Malkova, Anna
Format: Article
Language:English
Subjects:
Biology
Biomedical research
Cancer
Cell division
Chromosomes
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded
DNA Copy Number Variations - genetics
DNA repair
DNA Repair - genetics
DNA Replication - genetics
Experiments
Genetic aspects
Genomes
Genomic Instability
Genomics
Humans
Hybridization
Neoplasms - etiology
Neoplasms - genetics
Recombination, Genetic
Saccharomyces cerevisiae
Somatotropin
Telomere - genetics
Telomere - pathology
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Summary:Break-induced replication (BIR) is a mechanism to repair double-strand breaks (DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities including mutations, loss of heterozygosity, deletions, duplications, and template switching that can result in copy-number variations (CNVs). An important type of genomic rearrangement specifically linked to BIR is half-crossovers (HCs), which result from fusions between parts of recombining chromosomes. Because HC formation produces a fused molecule as well as a broken chromosome fragment, these events could be highly destabilizing. Here we demonstrate that HC formation results from the interruption of BIR caused by a damaged template, defective replisome or premature onset of mitosis. Additionally, we document that checkpoint failure promotes channeling of BIR into half-crossover-initiated instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. We postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1004119