Cascades of genetic instability resulting from compromised break-induced replication

Soumini Vasan; Angela Deem; Sreejith Ramakrishnan; Juan Lucas Argueso; Anna Malkova

doi:10.1371/journal.pgen.1004119

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Cascades of genetic instability resulting from compromised break-induced replication

Journal article

Open access

Peer reviewed

Cascades of genetic instability resulting from compromised break-induced replication

Soumini Vasan, Angela Deem, Sreejith Ramakrishnan, Juan Lucas Argueso and Anna Malkova

PLoS genetics, Vol.10(2), pp.e1004119-e1004119

02/2014

DOI: 10.1371/journal.pgen.1004119

PMCID: PMC3937135

PMID: 24586181

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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.

Genomic Instability

Telomere - pathology

Neoplasms - etiology

Neoplasms - genetics

Recombination, Genetic

Humans

DNA Replication - genetics

DNA Copy Number Variations - genetics

DNA Repair - genetics

DNA Breaks, Double-Stranded

Saccharomyces cerevisiae

Telomere - genetics

Details

Title: Subtitle: Cascades of genetic instability resulting from compromised break-induced replication
Creators: Soumini Vasan - Department of Biology, School of Science, IUPUI, Indianapolis, Indiana, United States of America
Angela Deem - Department of Biology, School of Science, IUPUI, Indianapolis, Indiana, United States of America
Sreejith Ramakrishnan - Department of Biology, School of Science, IUPUI, Indianapolis, Indiana, United States of America
Juan Lucas Argueso - Department of Environmental and Radiological Health Sciences Colorado State University, Fort Collins, Colorado, United States of America
Anna Malkova - Department of Biology, School of Science, IUPUI, Indianapolis, Indiana, United States of America ; Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.10(2), pp.e1004119-e1004119
DOI: 10.1371/journal.pgen.1004119
PMID: 24586181
PMCID: PMC3937135
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: United States
Grant note: R01GM084242 / NIGMS NIH HHS
Language: English
Date published: 02/2014
Academic Unit: Biology
Record Identifier: 9983991985402771

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