title: Genome-wide redistribution of H3K27me3 is linked to genotoxic stress and defective growth.
abstract: H3K9 methylation directs heterochromatin formation by recruiting multiple heterochromatin protein 1 (HP1)-containing complexes that deacetylate histones and methylate cytosine bases in DNA. In Neurospora crassa, a single H3K9 methyltransferase complex, called the DIM-5,-7,-9, CUL4, DDB1 Complex (DCDC), is required for normal growth and development. DCDC-deficient mutants are hypersensitive to the genotoxic agent methyl methanesulfonate (MMS), but the molecular basis of genotoxic stress is unclear. We found that both the MMS sensitivity and growth phenotypes of DCDC-deficient strains are suppressed by mutation of embryonic ectoderm development or Su-(var)3-9; E(z); Trithorax (set)-7, encoding components of the H3K27 methyltransferase Polycomb repressive complex-2 (PRC2). Trimethylated histone H3K27 (H3K27me3) undergoes genome-wide redistribution to constitutive heterochromatin in DCDC- or HP1-deficient mutants, and introduction of an H3K27 missense mutation is sufficient to rescue phenotypes of DCDC-deficient strains. Accumulation of H3K27me3 in heterochromatin does not compensate for silencing; rather, strains deficient for both DCDC and PRC2 exhibit synthetic sensitivity to the topoisomerase I inhibitor Camptothecin and accumulate γH2A at heterochromatin. Together, these data suggest that PRC2 modulates the response to genotoxic stress.
authors.affiliation: Department of Microbiology, University of Georgia, Athens, GA 30602;
authors.forename: Evelina Y
authors.initials: EY
authors.lastname: Basenko
authors.affiliation: Department of Microbiology, University of Georgia, Athens, GA 30602;
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Institute of Bioinformatics, University of Georgia, Athens, GA 30602;
authors.forename: Lexiang
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Microbiology, University of Georgia, Athens, GA 30602;
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Prybol
authors.affiliation: Department of Microbiology, University of Georgia, Athens, GA 30602;
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Burckhardt
authors.affiliation: Department of Genetics, University of Georgia, Athens, GA 30602.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmitz
authors.affiliation: Department of Microbiology, University of Georgia, Athens, GA 30602; zlewis@uga.edu.
authors.forename: Zachary A
authors.identifier: http://orcid.org/0000-0002-1735-8266
authors.initials: ZA
authors.lastname: Lewis
mesh_terms: D004249:DNA Damage; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D016681:Genome, Fungal; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009492:Neurospora crassa / Q000235:genetics / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D006570:Heterochromatin; D006657:Histones; D009097:Multienzyme Complexes; D011496:Protein Methyltransferases
keywords: H3K27me3; H3K9me3; Polycomb; genotoxic stress; heterochromatin