Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres.
During replicative aging of primary cells morphological transformations occur, the expression pattern is altered and chromatin changes globally. Here we show that chronic damage signals, probably caused by telomere processing, affect expression of histones and lead to their depletion. We investigated the abundance and cell cycle expression of histones and histone chaperones and found defects in histone biosynthesis during replicative aging. Simultaneously, epigenetic marks were redistributed across the phases of the cell cycle and the DNA damage response (DDR) machinery was activated. The age-dependent reprogramming affected telomeric chromatin itself, which was progressively destabilized, leading to a boost of the telomere-associated DDR with each successive cell cycle. We propose a mechanism in which changes in the structural and epigenetic integrity of telomeres affect core histones and their chaperones, enforcing a self-perpetuating pathway of global epigenetic changes that ultimately leads to senescence.
O'Sullivan
Roderick J
RJ
The Salk Institute for Biological Studies, Molecular and Cellular Biology Department, La Jolla, California, USA.
Kubicek
Stefan
S
Schreiber
Stuart L
SL
Karlseder
Jan
J
D001761:Bleomycin / Q000633:toxicity; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D004261:DNA Replication; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000096:biosynthesis*; D006801:Humans; D008745:Methylation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D009856:Oncogene Proteins, Viral / Q000502:physiology; D050725:Papillomavirus E7 Proteins / Q000502:physiology; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000502:physiology; D016160:Retinoblastoma Protein / Q000502:physiology; D016615:Telomere / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D039221:mRNA Cleavage and Polyadenylation Factors / Q000096:biosynthesis / Q000235:genetics
D002843:Chromatin; C068651:E6 protein, Human papillomavirus type 16; D006657:Histones; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C092663:SLBP protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D039221:mRNA Cleavage and Polyadenylation Factors; C059731:oncogene protein E7, Human papillomavirus type 16; D001761:Bleomycin