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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.

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Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA.
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Biology, University of Iowa, Iowa City, IA 52242, USA. Electronic address:


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.

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