Cascades of Genetic Instability Resulting from Compromised Break-Induced Replication

Soumini Vasan,Anna Malkova,Sreejith Ramakrishnan,Juan Lucas Argueso,Angela Deem,Philip J Hastings

doi:10.1371/journal.pgen.1004119

Abstract

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 we demonstrate that HC formation results from the interruption of BIR caused by a damaged template, defective replisome or premature onset of mitosis. Additionally, we document that checkpoint failure promotes channeling of BIR into half-crossover-initiated instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. We postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer.

Highlights

Double-strand DNA breaks (DSBs) are dangerous because they can lead to chromosomal rearrangements or cell death
Break-induced replication (BIR) is a mechanism of double-strand breaks (DSBs) repair that is often associated with deleterious events that can threaten genetic stability
One such deleterious event is the formation of halfcrossovers (HCs), which occurs when two chromosomes physically interacting during BIR repair fuse

Summary

Introduction

Double-strand DNA breaks (DSBs) are dangerous because they can lead to chromosomal rearrangements or cell death. DSBs may result from a cell’s exposure to various DNA-damaging agents, such as radiation and various chemicals, including anti-cancer drugs. DSB-induced changes to the genome have been implicated in promoting various human diseases, including cancer, which emphasizes the importance of proper repair of such lesions. Multiple pathways of DSB repair have evolved (reviewed in [1,2]). Homologous recombination (HR) mechanisms repair DSBs through recombination, where broken DNA ends initiate copying of a homologous sequence elsewhere within the genome. The most efficient pathway of HR is gene conversion (GC), where both ends of a DSB use a homologous sequence to copy lost DNA in order to repair the DSB lesion. Break-induced replication (BIR) is an HR mechanism that employs only a single end of a DSB for repair

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