![]() Such DSB resection is initiated by removal of a short 5’ DNA tract that requires the MRN complex and CtIP, while extensive resection requires BLM Hs (Sgs1 Sc, Rqh1 Sp), EXO1 and DNA2 ( 17–19). A distinguishing characteristic of HR repair is the enzymatic processing of the 5’ DNA end to reveal a single-stranded 3’ terminal sequence. Alternatively, HR defects may promote CIN by generating chromosomal bridges resulting from aberrant processing of one-ended DSBs arising from replication defects or through unresolved HR intermediates ( 14–16). Such dicentrics facilitate CIN through breakage fusion bridge cycles ( 13). Defective HR could potentially lead to CIN through C-NHEJ or alternative end-joining (A-NHEJ) of DSBs leading to dicentric chromosomal fusions ( 12). Such signatures are frequently found in breast cancers and ovarian cancers with mutations in or defective expression of BRCA1 or BRCA2 ( 11). Genomic analysis has linked somatic mutations in HR genes with significantly elevated levels of genomic CIN signatures, including loss of heterozygosity (LOH), copy number aberrations and tandem duplications. Importantly, impaired HR has recently been implicated as a major driver of CIN in a wide range of human cancer types ( 9, 10). DSBs are repaired by either canonical non-homologous end joining (C-NHEJ), homologous recombination (HR) or their alternative pathways, alternative end joining (Alt-EJ) or single-strand annealing (SSA), respectively ( 8). However, the underlying molecular events that drive structural CIN remain poorly understood.ĭNA double-strand break misrepair is a potential driver of CIN and cancer predisposition as highlighted by mutations in BRCA1, ATM, NBS1 and BLM being causal in cancer syndromes associated with CIN ( 7). The increased rate of such events associated with structural CIN appears to be driven through inappropriate mitotic segregation of broken, misrepaired or incompletely replicated chromosomes ( 6). Structural CIN refers to the increased frequency of large deletions, amplifications, translocations or other acquired chromosomal aberrations. Such increased chromosomal missegregation can result from distinct mechanisms including defects in chromosome cohesion, mitotic checkpoint function and centrosome copy number ( 5). Numerical CIN, in which the frequency of gain or loss of whole chromosomes is increased, reflects the loss of chromosome segregation fidelity in mitosis. Such heterogeneity has been proposed as a key factor contributing to the lethal outcome of cancer, therapeutic failure and drug resistance ( 4). Studies over the last century using cytogenetics, live-cell imaging and, more recently, whole genome sequencing (WGS) have revealed large scale inter- and intratumoural chromosomal abnormalities ( 2, 3). These findings reveal a mechanism by which HR genes suppress CIN and how DNA breaks that persist through mitotic divisions propagate cell-to-cell heterogeneity in the resultant progeny.Ĭhromosomal instability (CIN) increases the rate of numerical and structural chromosomal aberrations and is a hallmark of cancer ( 1). Subsequent propagation of unstable chromosomes carrying a single-ended DSB continues until transgenerational end-resection leads to fold-back inversion of single-stranded centromeric repeats and to stable chromosomal rearrangements, typically isochromosomes, or to chromosomal loss. These cycles are enabled by Cullin 3-mediated Chk1 loss and checkpoint adaptation. Inherited chromosomes carrying a single-ended DSB are subject to cycles of DNA replication and extensive end-processing across successive cell divisions. Further, we show that an unrepaired single-ended DSB arising from failed HR repair or telomere loss is a potent driver of widespread CIN. Using a fission yeast model system, we establish a common role for HR genes in suppressing DNA double-strand break (DSB)-induced CIN. Impaired homologous recombination (HR) has been implicated as a major driver of CIN, however, the underlying mechanism remains unclear. Chromosomal instability (CIN) drives cell-to-cell heterogeneity, and the development of genetic diseases, including cancer.
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