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Mol Cell. 2015 Dec 17;60(6):860-72. doi: 10.1016/j.molcel.2015.10.041. Epub 2015 Dec 6.

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

Author information

1
Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
2
Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA.
3
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Biology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: anna-malkova@uiowa.edu.

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.

PMID:
26669261
PMCID:
PMC4688117
DOI:
10.1016/j.molcel.2015.10.041
[Indexed for MEDLINE]
Free PMC Article

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