Abstract
Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD+-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse organisms; however, their molecular mechanisms in ageing regulation remain poorly understood. Yeast Sir2, the first member of the family to be found, establishes and maintains chromatin silencing by removing histone H4 lysine 16 acetylation and bringing in other silencing proteins. Here we report an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing by maintenance of intact telomeric chromatin.
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Acknowledgements
We thank E. Louis for providing strains for the telomere silencing assay, and members of the Kennedy and Kaeberlein labs who participated in lifespan-determination studies. This work was funded by US National Institutes of Health grants (S.L.B. and B.K.K.), and an American Federation for Aging Research Julie Martin Mid-Career Award in Aging Research (B.K.K.). M.K. is an Ellison Medical Foundation New Scholar in Aging.
Author Contributions Project planning was performed by W.D., F.B.J., A.S., B.K.K. and S.L.B; experimental work by W.D., K.K.S., R.P. and J.A.D.; data analysis by W.D.,K.K.S., F.B.J., M.K., B.K.K. and S.L.B.; and manuscript composition by W.D., F.B.J., M.K., B.K.K. and S.L.B.
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Dang, W., Steffen, K., Perry, R. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009). https://doi.org/10.1038/nature08085
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DOI: https://doi.org/10.1038/nature08085
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