Malkova, AnnaVasan, SouminiAtkinson, SimonKusmierczyk, Andrew2014-09-152014-09-152013https://hdl.handle.net/1805/5047http://dx.doi.org/10.7912/C2/2168Indiana 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.en-USComparative Genomic HybridizationBreak-induced ReplicationCopy Number VariationsChromosomal RearrangementsDouble-strand Break RepairHalf CrossoverHomologous RecombinationNon-reciprocal TranslocationHalf crossover instability cascadesDNA double-strand breakDNA repairGenetic instabilitiesArray-CGHDNA repair -- Research -- AnalysisDNA damage -- Research -- AnalysisDNA microarrays -- Research -- AnalysisDNA replication -- RegulationDNA -- AnalysisGenetic recombination -- ResearchMutagenesis -- ResearchMolecular biology -- ResearchMitosis -- Regulation -- ResearchDNA polymerasesDNA -- SynthesisHuman chromosome abnormalities -- ResearchTumors -- Genetic aspectsCancer -- Genetic aspectsThesis