Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements

Cynthia J Sakofsky; Sandeep Ayyar; Angela K Deem; Woo-Hyun Chung; Grzegorz Ira; Anna Malkova

doi:10.1016/j.molcel.2015.10.041

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Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements

Journal article

Open access

Peer reviewed

Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements

Cynthia J Sakofsky, Sandeep Ayyar, Angela K Deem, Woo-Hyun Chung, Grzegorz Ira and Anna Malkova

Molecular cell, Vol.60(6), pp.860-872

12/17/2015

DOI: 10.1016/j.molcel.2015.10.041

PMCID: PMC4688117

PMID: 26669261

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Abstract

Complex genomic rearrangements (CGRs) are a hallmark of many human diseases. Recently, CGRs were suggested to result from microhomology-mediated break-induced replication (MMBIR), a replicative mechanism involving template switching at positions of microhomology. Currently, the cause of MMBIR and the proteins mediating this process remain unknown. Here, we demonstrate in yeast that a collapse of homology-driven break-induced replication (BIR) caused by defective repair DNA synthesis in the absence of Pif1 helicase leads to template switches involving 0-6 nt of homology, followed by resolution of recombination intermediates into chromosomal rearrangements. Importantly, we show that these microhomology-mediated template switches, indicative of MMBIR, are driven by translesion synthesis (TLS) polymerases Polζ and Rev1. Thus, an interruption of BIR involving fully homologous chromosomes in yeast triggers a switch to MMBIR catalyzed by TLS polymerases. Overall, our study provides important mechanistic insights into the initiation of MMBIR associated with genomic rearrangements, similar to those promoting diseases in humans.

Chromosome Aberrations

Chromosomes, Fungal

DNA Breaks, Single-Stranded

DNA Helicases - metabolism

DNA Replication

DNA-Directed DNA Polymerase - metabolism

Genes, Fungal

Humans

Nucleotidyltransferases - metabolism

Saccharomyces cerevisiae - enzymology

Saccharomyces cerevisiae - genetics

Saccharomyces cerevisiae Proteins - metabolism

Sequence Homology

Details

Title: Subtitle: Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements
Creators: Cynthia J Sakofsky - Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Sandeep Ayyar - Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA
Angela K Deem - Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA
Woo-Hyun Chung - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Grzegorz Ira - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Anna Malkova - Department of Biology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: anna-malkova@uiowa.edu
Resource Type: Journal article
Publication Details: Molecular cell, Vol.60(6), pp.860-872
DOI: 10.1016/j.molcel.2015.10.041
PMID: 26669261
PMCID: PMC4688117
ISSN: 1097-2765
eISSN: 1097-4164
Grant note: R01 GM080600 / NIGMS NIH HHS GM080600 / NIGMS NIH HHS R01 GM084242 / NIGMS NIH HHS R01GM084242 / NIGMS NIH HHS
Language: English
Date published: 12/17/2015
Academic Unit: Biology
Record Identifier: 9984217525402771

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