title: Deposition of histone H2A.Z by the SWR-C remodeling enzyme prevents genome instability.
abstract: The yeast SWR-C chromatin remodeling enzyme catalyzes chromatin incorporation of the histone variant H2A.Z which plays roles in transcription, DNA repair, and chromosome segregation. Dynamic incorporation of H2A.Z by SWR-C also enhances the ability of exonuclease I (Exo1) to process DNA ends during repair of double strand breaks. Given that Exo1 also participates in DNA replication and mismatch repair, here we test whether SWR-C influences DNA replication fidelity. We find that inactivation of SWR-C elevates the spontaneous mutation rate of a strain encoding a L612M variant of DNA polymerase (Pol) δ, with a single base mutation signature characteristic of lagging strand replication errors. However, this genomic instability does not solely result from reduced Exo1 function, because single base mutator effects are seen in both Exo1-proficient and Exo1-deficient pol3-L612M swr1Δ strains. The data are consistent with the possibility that incorporation of the H2A.Z variant by SWR-C may stimulate Exo1 activity, as well as enhance the fidelity of replication by Pol δ, the repair of mismatches generated by Pol δ, or both.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Van
authors.affiliation: Laboratory of Structural Biology and Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC 27709, United States.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Williams
authors.affiliation: Laboratory of Structural Biology and Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC 27709, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States. Electronic address: Craig.Peterson@umassmed.edu.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Peterson
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D053843:DNA Mismatch Repair; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D004271:DNA, Fungal / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins; D059645:Mutation Rate; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D004271:DNA, Fungal; D006657:Histones; C493530:Htz1 protein, S cerevisiae; D050505:Mutant Proteins; C491232:POL3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D004258:DNA Polymerase III; D005090:Exodeoxyribonucleases; C028450:exodeoxyribonuclease I; D000251:Adenosine Triphosphatases; C481261:Swr1 protein, S cerevisiae
keywords: Chromatin remodeling; Exonuclease 1; Genome instability; H2A.Z; Mismatch repair