Abstract
Genetic instabilities, including mutations and chromosomal rearrangements, lead to cancer and other diseases in humans and play an important role in evolution. A frequent cause of genetic instabilities is double-strand DNA breaks (DSBs), which may arise from a wide range of exogeneous and endogeneous cellular factors. Although the repair of DSBs is required, some repair pathways are dangerous because they may destabilize the genome. One such pathway, break-induced replication (BIR), is the mechanism for repairing DSBs that possesses only one repairable end. This situation commonly arises as a result of eroded telomeres or collapsed replication forks. Although BIR plays a positive role in repairing DSBs, it can alternatively be a dangerous source of several types of genetic instabilities, including loss of heterozygosity, telomere maintenance in the absence of telomerase, and non-reciprocal translocations. Also, mutation rates in BIR are about 1000 times higher as compared to normal DNA replication. In addition, micro-homology-mediated BIR (MMBIR), which is a mechanism related to BIR, can generate copy-number variations (CNVs) as well as various complex chromosomal rearrangements. Overall, activation of BIR may contribute to genomic destabilization resulting in substantial biological consequences including those affecting human health.
Highlights
Genomic instability leading to mutations and chromosomal rearrangements can enable pre-cancerous cells to acquire many hallmarks of cancer, such as limitless replicative potential, evasion of cell death and constant proliferation
No clear explanation for the origin of genetic instability exists, the activation of oncogenes in pre-cancerous cells have been found to lead to over-initiation of replication which results in the collapse of replication forks [1,2,3,4], the accumulation of DNA breaks, and a burst of genetic instability [1,3,4,5,6]; reviewed in [7,8]
break-induced replication (BIR) has yet to be studied in mammals, some evidence has suggested that it operates in humans, and that its activation is a probable cause of many human diseases
Summary
Genomic instability leading to mutations and chromosomal rearrangements can enable pre-cancerous cells to acquire many hallmarks of cancer, such as limitless replicative potential, evasion of cell death and constant proliferation. BIR is a DSB repair mechanism capable of recovering collapsed replication forks that is known to produce genomic rearrangements and genetic mutations at high frequencies. BIR, which was originally discovered and investigated in bacteria and viruses, has recently been thoroughly studied using yeast Saccharomyces cerevisiae, a model eukaryotic organism. Studies in yeast have provided details of molecular mechanisms, regulation, and proteins participating in BIR, as well as analyses of genetic instabilities resulting from BIR. We use the data obtained from yeast to discuss mechanisms of BIR and to explain the reasons for genetic instabilities resulting from this DNA repair pathway. We examine recent evidence which connects microhomology-mediated BIR (MMBIR), a BIR-related mechanism, to human diseases
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