Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres
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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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Autophagy-mediated CCF formation together with reduced histone synthesis might lead to global loss of core histones during senescence, affecting the chromatin landscape.
“Autophagy-mediated CCF formation (Dou et al., 2015) together with reduced histone synthesis (O'Sullivan et al., 2010) might also lead to a global loss of core histones during senescence, affecting the chromatin landscape (Chan and Narita, 2019; Ivanov et al., 2013).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as O'Sullivan et al., 2010
Damaged telomeres can lead to reduction in core histone expression, suggesting loss of telomere integrity can cause changes in aging chromatin landscape.
“Interestingly, damaged telomeres can also lead to a reduction in the expression of core histones in a cell, suggesting that a loss of telomere integrity can cause changes in the aging chromatin landscape (O’Sullivan et al., 2010).”
From The Aging Epigenome (2016) · cites this paper as O’Sullivan et al., 2010
ARCH is associated with an increased risk of a subsequent haematological malignancy and with an almost twofold increased risk of cardiovascular mortality.
“Strikingly, ARCH is associated with an increased risk of a subsequent haematological malignancy and with an almost twofold increased risk of cardiovascular mortality 76-78 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [76]
Mutations in genes encoding DNMT3A, TET2 and ASXL1 account for greater than 70% of cases of ARCH.
“Mutations in genes encoding DNMT3A, TET2 (Supplementary Table 1) and additional sex-combs like 1 (ASXL1), which regulate DNA and histone methylation, account for greater than 70% of cases of ARCH 76-78 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [76]
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- Authors
- O'Sullivan, R. J., Kubicek, S., Schreiber, S. L., & Karlseder, J.
- Affiliations
- Broad Institute (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Karlseder, Jan
- Venue
- Nature Structural & Molecular Biology
- Published
- 2010-10
- Volume
- 17
- Issue
- 10
- Pages
- 1218-1225
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC2951278
- OpenAlex
- W2062947816
- Cited by
- 416
- References
- 59
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 24 · 2023: 22 · 2022: 23 · 2021: 27 · 2020: 37 · 2019: 41 · 2018: 35 · 2017: 29 · 2016: 26 · 2015: 21 · 2014: 25 · 2013: 35 · 2012: 24
- FWCI
- 16.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- George E. Hewitt Foundation for Medical Research
- European Commission
- Ernst Schering Foundation
- National Institute on Aging (R01AG025837)
- National Institute of General Medical Sciences (R01GM069525, R01 GM06525, R01GM087476)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- telomere shortening, replicative senescence, aging, histone biosynthesis, histone chaperone, Asf1, DNA damage response, epigenetic reprogramming, telomeric chromatin, cell cycle, histone depletion
- MeSH terms
- Bleomycin, Cell Line, Chromatin, DNA Damage, DNA Replication, Fibroblasts, Histones, Humans, Methylation, Nuclear Proteins, Oncogene Proteins, Viral, Protein Processing, Post-Translational, Repressor Proteins, Tumor Suppressor Protein p53, Retinoblastoma Protein, Telomere, Cellular Senescence, mRNA Cleavage and Polyadenylation Factors, Epigenesis, Genetic, Chromatin Immunoprecipitation, Papillomavirus E7 Proteins
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