title: Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements.
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.
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Sakofsky
authors.affiliation: Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Ayyar
authors.affiliation: Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Deem
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Woo-Hyun
authors.initials: WH
authors.lastname: Chung
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Ira
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: anna-malkova@uiowa.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Malkova
mesh_terms: D002869:Chromosome Aberrations; D015825:Chromosomes, Fungal; D053904:DNA Breaks, Single-Stranded; D004265:DNA Helicases / Q000378:metabolism; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005800:Genes, Fungal; D006801:Humans; D009713:Nucleotidyltransferases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D017385:Sequence Homology; D000099270:Y-Family DNA Polymerases
chemical_list: D004265:DNA Helicases; D004259:DNA-Directed DNA Polymerase; D009713:Nucleotidyltransferases; D029701:Saccharomyces cerevisiae Proteins; C425929:DNA polymerase zeta; C100951:REV1 protein, S cerevisiae; D000099270:Y-Family DNA Polymerases; C085463:PIF1 protein, S cerevisiae