Break-Induced Replication and Genome Stability

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.

DNA-Pairing and Annealing Processes in Homologous Recombination and Homology-Directed Repair

“…BIR may proceed for many kilobases, resulting in extensive GC tracts or in the duplication of an entire chromosome arm. For this reason BIR is associated with extensive LOH (Sakofsky et al 2012). …”

Reversible Mitochondrial DNA Accumulation in Nuclei of Pluripotent Stem Cells

“…S6). The extrachromosomal mtDNA circles may be maintained and inherited in the nucleus by break-induced replication mechanisms [56,57]. (3) Another possible scenario is that a few single fibroblasts with already highly amplified mtDNA molecules in the nucleus may be the preferential source for the reprogramming to iPS cells.…”

DNA polymerases are error-prone at RecA-mediated recombination intermediates

“…Consistent with this idea, several studies of yeast demonstrate that a long tract form of RDR called break-induced replication (BIR) is highly error-prone and involves template-switching events. 11,[28][29][30] …”

“…Consistent with this idea, high-fidelity B-family replicative pol δ promotes low-fidelity DNA synthesis during gene conversion and break-induced replication (BIR) in budding yeast. 11,28,29,37 BIR also occurs at telomeres in yeast and mammalian cells-a process called alternative lengthening of telomeres (ALT). Altogether, error-prone RDR has been well documented in bacteria and eukaryotes and in both cases high-fidelity DNA polymerases promote mutations during homologous recombination regardless of their ability to promote accurate DNA synthesis on primer templates.…”

“…This recombination-directed replication (RDR) process is often referred to as D-loop extension or break-induced replication (BIR), which is also error-prone in yeast. 11 Pol IV involvement in errorprone RDR (stress-induced mutagenesis) requires upregulation of the polymerase by the SOS response and induction of the RpoS stress response, which occurs in stationary-phase cells (Fig. 1).…”