title: Methylation of histone H3K23 blocks DNA damage in pericentric heterochromatin during meiosis.
abstract: Despite the well-established role of heterochromatin in protecting chromosomal integrity during meiosis and mitosis, the contribution and extent of heterochromatic histone posttranslational modifications (PTMs) remain poorly defined. Here, we gained novel functional insight about heterochromatic PTMs by analyzing histone H3 purified from the heterochromatic germline micronucleus of the model organism Tetrahymena thermophila. Mass spectrometric sequencing of micronuclear H3 identified H3K23 trimethylation (H3K23me3), a previously uncharacterized PTM. H3K23me3 became particularly enriched during meiotic leptotene and zygotene in germline chromatin of Tetrahymena and C. elegans. Loss of H3K23me3 in Tetrahymena through deletion of the methyltransferase Ezl3p caused mislocalization of meiosis-induced DNA double-strand breaks (DSBs) to heterochromatin, and a decrease in progeny viability. These results show that an evolutionarily conserved developmental pathway regulates H3K23me3 during meiosis, and our studies in Tetrahymena suggest this pathway may function to protect heterochromatin from DSBs.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States Center for Epigenetics, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Romeo
authors.initials: R
authors.lastname: Papazyan
authors.affiliation: Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Balitmore, United States Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Voronina
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, United States.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Chapman
authors.affiliation: Center for Epigenetics, The Johns Hopkins University School of Medicine, Baltimore, United States Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Teresa R
authors.initials: TR
authors.lastname: Luperchio
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States Center for Epigenetics, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Tonya M
authors.initials: TM
authors.lastname: Gilbert
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States Center for Epigenetics, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Meier
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, United States.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Mackintosh
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shabanowitz
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, United States.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Tackett
authors.affiliation: Center for Epigenetics, The Johns Hopkins University School of Medicine, Baltimore, United States Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Reddy
authors.affiliation: Department of Genomic Medicine, J. Craig Venter Institute, Rockville, United States.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Coyne
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, United States Department of Pathology, University of Virginia, Charlottesville, United States.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hunt
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States Center for Epigenetics, The Johns Hopkins University School of Medicine, Baltimore, United States staverna@jhmi.edu.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Taverna
mesh_terms: D000595:Amino Acid Sequence; D053903:DNA Breaks, Double-Stranded; D016054:DNA, Protozoan / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008540:Meiosis / Q000235:genetics; D008745:Methylation; D048631:Micronucleus, Germline / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D016808:Tetrahymena thermophila / Q000235:genetics / Q000378:metabolism*
chemical_list: D016054:DNA, Protozoan; D006570:Heterochromatin; D006657:Histones; D015800:Protozoan Proteins; D011495:Histone-Lysine N-Methyltransferase
keywords: DNA damage; Tetrahymena thermophila; chromatin; histones; meiosis; methylation