Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres

• Published in: Nature structural & molecular biology Vol. 17; no. 10; pp. 1218 - 1225
• Main Authors: O'Sullivan, Roderick J, Kubicek, Stefan, Schreiber, Stuart L, Karlseder, Jan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2010; Nature Publishing Group
• Subjects: 631/337/100/102; 631/337/103/560; 631/337/1427/2566; 631/337/641; Aging; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Biosynthesis; Bleomycin - toxicity; Cell cycle; Cell Line; Cellular biology; Cellular Senescence - physiology; Chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation; Deoxyribonucleic acid; DNA; DNA Damage; DNA Replication; Epigenesis, Genetic; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Genetic aspects; Histones; Histones - biosynthesis; Humans; Life Sciences; Membrane Biology; Methylation; Molecular biology; mRNA Cleavage and Polyadenylation Factors - biosynthesis; mRNA Cleavage and Polyadenylation Factors - genetics; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Oncogene Proteins, Viral - physiology; Papillomavirus E7 Proteins - physiology; Physiological aspects; Protein Processing, Post-Translational; Protein Structure; Repressor Proteins - physiology; Retinoblastoma Protein - physiology; Signal transduction; Telomere - physiology; Telomeres; Tumor Suppressor Protein p53 - physiology; United States
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/nsmb.1897

Telomere shortening, senescence and aging are connected, but how the signal at shortening telomeres is transmitted to the cell more globally is unclear. H3 and H4 synthesis is now shown to be reduced as cell cultures age. This alters expression of Asf1, a histone chaperone, compromising the ability of aging cells to restore chromatin after replication and DNA. In this way localized effects at shortening telomeres can be propagated throughout the cell. 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.