title: An H2A Histone Isotype, H2ac, Associates with Telomere and Maintains Telomere Integrity.
abstract: Telomeres are capped at the ends of eukaryotic chromosomes and are composed of TTAGGG repeats bound to the shelterin complex. Here we report that a replication-dependent histone H2A isotype, H2ac, was associated with telomeres in human cells and co-immunoprecipitates with telomere repeat factor 2 (TRF2) and protection of telomeres protein 1 (POT1), whereas other histone H2A isotypes and mutations of H2ac did not bind to telomeres or these two proteins. The amino terminal basic domain of TRF2 was necessary for the association with H2ac and for the recruitment of H2ac to telomeres. Depletion of H2ac led to loss of telomeric repeat sequences, the appearance of dysfunctional telomeres, and chromosomal instability, including chromosomal breaks and anaphase bridges, as well as accumulation of telomere-associated DNA damage factors in H2ac depleted cells. Additionally, knockdown of H2ac elicits an ATM-dependent DNA damage response at telomeres and depletion of XPF protects telomeres against H2ac-deficiency-induced G-strand overhangs loss and DNA damage response, and prevents chromosomal instability. These findings suggest that the H2A isotype, H2ac, plays an essential role in maintaining telomere functional integrity.
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, 11221, Taiwan, Republic of China.
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Su
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, 11221, Taiwan, Republic of China.
authors.forename: Ching
authors.initials: C
authors.lastname: Cheng
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, University System of Taiwan, Taipei, 11221, Taiwan, Republic of China.
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Tzeng
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, 11221, Taiwan, Republic of China.
authors.forename: I-Hsuan
authors.initials: IH
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, 11221, Taiwan, Republic of China.|VYM Genome Research Center, National Yang-Ming University, University System of Taiwan, Taipei, 11221, Taiwan, Republic of China.|Chien-Tien Hsu Cancer Research Foundation, Taipei, 11221, Taiwan, Republic of China.
authors.forename: Ming-Ta
authors.initials: MT
authors.lastname: Hsu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability / Q000502:physiology; D004249:DNA Damage; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000502:physiology*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; C440849:POT1 protein, human; D020033:Protein Isoforms; D000089804:Shelterin Complex; C504753:TERF2 protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins