DNA damage-induced alterations in chromatin contribute to genomic integrity and age-related changes in gene expression

By Philipp Oberdoerffer, Shaday Michán, Michael McVay, R. Mostoslavsky, J. Vann, Sang-Kyu Park, A. Hartlerode, Judith Stegmuller, A. Hafner, P. Loerch and 8 more. Cell, 2008

791 citations recorded by the source corpus.

Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin modifying proteins may be a conserved mechanism of aging in eukaryotes.

Subfields: Aging, Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5a0c011269f22aa7b4eef371990333d7b46f3cf4

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In Aging

1. Guido Kroemer
2. Manuel Serrano
3. Linda Partridge
4. M. Blasco
5. D. Sinclair
6. J. Tyler
7. Brian J. North
8. Nicholas A. Bishop

In Geriatrics and Gerontology

1. Joseph A. Baur
2. D. Sinclair
3. W. Kraus
4. Guido Kroemer
5. Brian J. North
6. Nicholas A. Bishop
7. T. Arnesen
8. Rasmus Ree

In Molecular Biology

1. Linda Partridge
2. S. Polo
3. W. Kraus
4. Manuel Serrano
5. Li-Huei Tsai
6. L. Pan
7. R. Madabhushi
8. Guido Kroemer

Citations in the corpus

• Neural mechanisms of ageing and cognitive decline (2010, background): “Recent studies have shown that DNA damage can induce changes in gene expression and histone modification patterns that may be mediated, in part, by the conserved lifespan regulatory gene SIRT1 (see below), suggesting a possible mechanistic link between DNA damage, epigenomic state and agein”
• The hallmarks of aging. (2013, background): “The mechanisms involved in the beneficial effects of SIRT1 are complex and interconnected, including improved genomic stability (Oberdoerffer et al., 2008; Wang et al., 2008) and enhanced metabolic efficiency (Nogueiras et al., 2012) (see ‘‘Deregulated Nutrient Sensing’’).”
• The world of protein acetylation. (2016, background): “protein may offer protection from the effects of DNA damage [440].”
• Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “Through its interaction with RAD51, BRCA2 in turn promotes RAD51 assembly onto ssDNA (Jensen et al. 2010; J Liu et al. 2010; Thorslund et al. 2010).”
• Epigenetics and aging (2016, background): “Therefore, repression of heterochromatic repeat elements seems to be evolutionarily conserved and extremely critical in life span maintenance (33, 35).”
• SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “Further supporting a role in genetic stability, SIRT1 / embryos exhibit impaired DNA repair and increased chromosomal abnormalities (348), while overexpression of SIRT1 reduces aneuploidy and delays lymphoma (235).”