title: Decrease of p400 ATPase complex and loss of H2A.Z within the p21 promoter occur in senescent IMR-90 human fibroblasts.
abstract: Replicative senescence in human diploid fibroblasts is characterised by an exhaustion of proliferative potential and permanent cell cycle arrest. During senescence, telomere shortening-generated DNA damage activates p53 pathway that upregulates cell cycle inhibitors, such as p21. Human p400 ATPase is a chromatin remodeller that plays a key role in the deposition of the histone variant, H2A.Z within the p21 promoter, repressing p21 gene expression. Decline of p400 ATPase in senescent IMR-90 cells prompted us to investigate structural changes in the chromatin of the p21 promoter during in vitro aging. Whereas doxorubicin treatment in early-passaged cells results in nucleosome density changes near the p53 binding sites of the p21 promoter, our studies show that senescent cells with a high p21 transcription activity had a comparable nucleosome distribution as unstressed young cells. However, H2A.Z that is highly enriched within the p21 promoter of young cells is depleted in senescent cells, suggesting that downregulation of p400 and loss of H2A.Z localisation play roles in relieving p21 gene repression in senescent IMR-90 cells. Taken together, our results indicate that age-dependent p400 downregulation and loss of H2A.Z localisation may contribute to the onset of replicative senescence through a sustained high rate of p21 transcription.
authors.affiliation: Institute of Molecular BioSciences, Massey University, Palmerston North, New Zealand.
authors.forename: Kangmoon
authors.initials: K
authors.lastname: Lee
authors.forename: Zin Zee
authors.initials: ZZ
authors.lastname: Lau
authors.forename: Courtney
authors.initials: C
authors.lastname: Meredith
authors.forename: Jeong Hyeon
authors.initials: JH
authors.lastname: Park
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry*; D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D016158:Genes, p53; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008836:Micrococcal Nuclease / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017382:Reactive Oxygen Species; D016615:Telomere / Q000648:ultrastructure; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006657:Histones; D009707:Nucleosomes; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C077020:histone H2A.F-Z; D008836:Micrococcal Nuclease; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; C498558:EP400 protein, human