Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence

By Graeme Hewitt, D. Jurk, F. Marques, C. Correia-Melo, T. Hardy, A. Gackowska, Rhys K. Anderson, Morgan L. Taschuk, J. Mann, J. Passos. Nature Communications, 2012

865 citations recorded by the source corpus.

Telomeres are specialized nucleoprotein structures, which protect chromosome ends and have been implicated in the ageing process. Telomere shortening has been shown to contribute to a persistent DNA damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells. Similarly, persistent DDR foci can be found in stress-induced senescence, although their nature is not understood. Here we show, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress-induced senescence are located at telomeres irrespective of telomerase activity. Moreover, live-cell imaging experiments reveal that all persistent foci are associated with telomeres. Finally, we report an age-dependent increase in frequencies of telomere-associated foci in gut and liver of mice, occurring irrespectively of telomere length. We conclude that telomeres are important targets for stress in vitro and in vivo and this has important consequences for the ageing process. Irreparable DNA damage leads to apoptosis or senescence. Hewittet al. show that, in response to genotoxic or oxidative stress, DNA damage occurs predominantly at telomere associated foci, which accumulate with age in vivo, irrespective of telomerase activity.

Subfields: Aging, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/171aba972c0932709f70471238feda324c5992ec

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

In Molecular Biology

In Physiology

Citations in the corpus

Aging, Cellular Senescence, and Cancer (2012, background): “Indeed, aging tissues show a steady accumulation of cells that harbor DNA damage foci, similar to the foci that are found in senescent cells (29, 30, 144).”
Mitochondrial dysfunction in cell senescence and aging (2022, background): “Telomere dysfunction might be caused by telomere shortening during DNA replication (3, 4), replication-independent telomere damage (5), or a variety of other stresses (6).”
Cellular senescence mediates fibrotic pulmonary disease (2017, positive): “X and telomere immuno-ﬂuorescence in situ hybridization co-localization 25 .”
Cellular senescence and its effector programs (2014, background): “, by g-irradiation), damage within telomeres is irreparable and thus stabilized (Fumagalli et al. 2012; Hewitt et al. 2012; Suram et al. 2012).”
Cellular senescence drives age-dependent hepatic steatosis (2017, neutral): “X with a telomere PNA probe assessed by immuno-ﬂuorescent in situ hybridization (FISH)) increase with age in mouse hepatocytes 17 .”
Measuring biological aging in humans: A quest (2019, result): “New methods are being developed, some of which are focused on detecting the DNA damage response (a typical marker of critical telomere shortening) may yield better results (Choi, Kim, Kim, Kemp, & Sancar, 2015; Hewitt et al., 2012; Rossiello et al., 2017).”
The hallmarks of aging. (2013, background): “Due to their restricted DNA repair, DNA damage at telomeres is notably persistent and highly efficient in inducing senescence and/or apoptosis (Fumagalli et al., 2012; Hewitt et al., 2012).”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “In addition, senescent cells are commonly characterized by an altered cell size with a more smoothed shape compared with proliferating cells and exhibit senescence-associated heterochromatin foci formation (242), accumulation of lipofuscin (136), DNA damage foci (159), loss of lamin B1 (296), senesc”
G-quadruplexes and their regulatory roles in biology (2015, background): “Genome-wide analysis of DNA breakpoints in different cancer types show a significant enrichment in pG4s in the vicinity of somatic copy number alterations (22), as well as telomeres being favoured targets of persistent DNA damage response in aging (23).”
Mechanisms of DNA damage, repair and mutagenesis (2017, neutral): “For example, short telomeres often assemble DDR factors such as 53BP1, ATM, gH2AX, and MRE11 as foci, called Telomere Dysfunction-Induced Foci, which are highly prone to NHEJ-mediated end-to-end fusion [Takai et al., 2003; Hewitt et al., 2012; Marcand, 2014].”