Abstract
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.
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Acknowledgements
We thank G. Almouzni (Institut Curie) for sharing antibodies to Asf1a and Asf1b and for helpful discussions. We are grateful to T. Jenuwein (Max Planck Institute of Immunobiology) for the gift of the H3K9, H3K27 and H4K20 series of antibodies, T. Hunter (Salk Institute) for cyclin antibodies, T. de Lange (The Rockefeller University) for advice on chronic damage protocols, J. Jaffe (Broad Institute) and S. Carr (Broad Institute) for access to the Broad Proteomics Platform, expert advice and helpful discussion. We also thank D. Chambers (Salk Institute) and J. Barrie (Salk Institute) for technical assistance with flow cytometry. We are grateful to members of the Karlseder lab for critical discussion of the manuscript. R.J.O'S. is supported by the George E. Hewitt Foundation for Medical Research, S.K. is supported by a postdoctoral fellowship of the Ernst Schering Research Foundation and the European Union, and J.K. acknowledges support by the US National Institutes of Health (RO1 GM06525 and RO1 AG025837).
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R.J.O'S. designed and carried out experiments and wrote the manuscript, S.K. did the MS analysis, S.L.S. provided advice and access to the MS facilities, and J.K. designed experiments and wrote the manuscript.
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O'Sullivan, R., Kubicek, S., Schreiber, S. et al. Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struct Mol Biol 17, 1218–1225 (2010). https://doi.org/10.1038/nsmb.1897
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DOI: https://doi.org/10.1038/nsmb.1897
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