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1	Cascades of genetic instability resulting from compromised break-induced replication Vasan, Soumini January 2013 (has links) Indiana University-Purdue University Indianapolis (IUPUI) / 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 I demonstrate that HC formation results from the interruption of BIR caused by a defective replisome or premature onset of mitosis. Additionally, I document the existence of half crossover instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. I postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer. Comparative Genomic Hybridization Break-induced Replication Copy Number Variations Chromosomal Rearrangements Double-strand Break Repair Half Crossover Homologous Recombination Non-reciprocal Translocation Half crossover instability cascades DNA double-strand break DNA repair Genetic instabilities Array-CGH DNA repair -- Research -- Analysis DNA damage -- Research -- Analysis DNA microarrays -- Research -- Analysis DNA replication -- Regulation DNA -- Analysis Genetic recombination -- Research Mutagenesis -- Research Molecular biology -- Research Mitosis -- Regulation -- Research DNA polymerases DNA -- Synthesis Tumors -- Genetic aspects Cancer -- Genetic aspects

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Cascades of genetic instability resulting from compromised break-induced replication