DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?

Passos, João F.; Saretzki, Gabriele; Zglinicki, Thomas von

doi:10.1093/nar/gkm893

Cited by 294 publications

(234 citation statements)

References 123 publications

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“…Dysfunctional telomeres are recognized as DNA double-stranded breaks, thereby activating the DNA damage response program (21). Stress-induced senescence can occur in both mortal and immortal cells via exposure to DNA damage, chromatin remodeling, oxidative stress, oncogenic stress, and strong mitogenic responses (22)(23)(24). Although endogenous replicative senescence and exogenous stress-induced stem from completely different origins, both processes demonstrate strong similarities with regard to activation of DNA damage response and repair programs and thus inducing cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

Hasan

Cheung

Kaul

et al. 2009

Journal of Biological Chemistry

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The tumor suppressor protein, p53, is central to the pathways that monitor the stress, DNA damage repair, cell cycle, aging, and cancer. Highly complex p53 networks involving its upstream sensors and regulators, downstream effectors and regulatory feedback loops have been identified. CARF (Collaborator of ARF) was shown to enhance ARF-dependent and -independent wild-type p53 function. Here we report that (i) CARF overexpression causes premature senescence of human fibroblasts, (ii) it is vital for replicative and stress-induced senescence, and (iii) the lack of CARF function causes aneuploidy and apoptosis. We provide evidence that CARF plays a dual role in regulating p53-mediated senescence and apoptosis, the two major tumor suppressor mechanisms.The tumor suppressor protein, p53, is the most frequently inactivated protein in human cancers that symbolizes deregulation of genomic stability, cell cycle, senescence, and stress damage-repair response of cells (1-5). p53 signaling has been established as a complex network comprised of (i) upstream components consisting of stress signals and sensor proteins including kinases, transferases, methyalses, ligases, and others that regulate its activity either by post-translational modifications or by subcellular localization, (ii) core regulators including an upstream positive regulator (alternative reading frame, ARF) 4 protein that blocks its downstream effector and antagonist human double minute-2 (HDM2) protein, and (iii) the downstream effectors that determine the fate of cells by instigation of growth arrest, senescence, or apoptosis, the three potent tumor suppressor mechanisms. In addition to the fact that the initiation of DNA damage-induced senescence and establishment of growth arrest require p53 activation (4), a large number of studies have shown that the persistent inactivation of p53 is required for tumor maintenance. Cancer cells undergo either growth arrest or apoptosis with restoration of wild-type p53 function in vitro and in vivo (6 -8). These studies have prioritized further understanding of p53 signaling and regulation that would have major impact in cancer drug development.It is yet to be resolved how functional restoration of p53 culminates to growth arrest/senescence in some cells and apoptosis in others. Is it driven by the level of p53 expression, modulating partner proteins or its upstream regulators? Among the large number of p53-binding proteins that influence its activities, ARF and HDM2 have been demonstrated as its major regulators. HDM2 (an E3 ubiquitin ligase) is transcriptionally activated by p53 and acts to degrade p53 in turn; thus, executing a negative feedback loop on p53 activity. ARF has been shown to bind and inhibit HDM2 activity resulting in the activation of p53 pathway (9). CARF (Collaborator of ARF) protein was initially cloned as an ARF-binding protein by yeast two-hybrid screening and was shown to activate ARF-dependent and -independent p53 functions (10 -13). CARF interacts not only with ARF but also with p53 and HDM2, an...

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Section: Discussionmentioning

confidence: 99%

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

Hasan

Cheung

Kaul

et al. 2009

Journal of Biological Chemistry

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Section: Introductionmentioning

confidence: 99%

“…Genetic changes in the telomeres and mtDNA independently serve important roles in cellular senescence (18). mtDNA damage caused by cellular senescence may contribute to the production of reactive oxygen species (ROS), resulting in telomere shortening (18). Past reviews have emphasized the importance of the telomere-p53-mitochondrion axis for cancer, suggesting that this may be targeted in future cancer therapy (19,20).…”

Section: Introductionmentioning

confidence: 99%

Telomere length is correlated with mitochondrial DNA copy number in intestinal, but not diffuse, gastric cancer

et al. 2017

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Abstract.A positive correlation between telomere length and mitochondrial DNA (mtDNA) copy number has previously been observed in healthy individuals, and in patients with psychiatric disorders. In the present study, telomere length and mtDNA copy number were evaluated in gastric cancer (GC) tissue samples. DNA was extracted from 109 GC samples (including 82 intestinal, and 27 diffuse cases), and the telomere length and mtDNA copy number were analyzed using a quantitative-polymerase chain reaction assay. The relative telomere length and mtDNA copy number in tumor tissue, as compared with in normal tissue, (mean ± standard deviation) in all GC samples were 11.48±1.14 and 14.86±1.35, respectively. Telomere length and mtDNA copy number were not identified as exhibiting clinical or prognostic value for GC. However, positive correlations between telomere length and mitochondrial DNA copy number were identified in GC (r=0.408, P<0.001) and in the adjacent normal mucosa (r=0.363; P<0.001). When stratified by Lauren classification, the correlation was identified in intestinal type GC samples (r=0.461; P<0.001), but not in diffuse type GC samples (r= 0.225; P= 0.260). This result indicated that loss of the correlation of telomeres and mitochondrial function may induce the initiation or progression of GC pathogenesis.

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“…When energy requirements are low, they are selected for mitophagy or become inactive. Mitochondria vary in number from cell to cell, are highly prone to oxidative damage, lack efficient mtDNA repair mechanisms, and can accrue mutations and go unnoticed [11][12][13]. Abnormal accumulation of defective mitochondria in cells can trigger activation of senescence or apoptosis [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Burke

et al. 2010

j ocul biol dis inform

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Impairment of mitochondria function and cellular antioxidant systems are linked to aging and neurodegenerative diseases. In the eye, the retinal pigment epithelium (RPE) is exposed to a highly oxidative environment that contributes to age-related visual dysfunction. Here, we examined changes in mitochondrial function in human RPE cells and sensitivity to oxidative stress with increased chronological age. Primary RPE cells from young (9-20)-, mid-age (48-60)-, and >60 (62-76)-year-old donors were grown to confluency and examined by electron microscopy and flow cytometry using several mitochondrial functional assessment tools. Susceptibility of RPE cells to H 2 O 2 toxicity was determined by lactate dehydrogenase and cytochrome c release, as well as propidium iodide staining. Reactive oxygen species, cytoplasmic Ca 2+ [Ca 2+ ] c , and mitochondrial Ca 2+ [Ca 2+ ] m levels were measured using 2′,7′-dichlorodihydrofluorescein diacetate, fluo-3/AM, and Rhod-2/AM, respectively, adenosine triphosphate (ATP) levels were measured by a luciferin/luciferase-based assay and mitochondrial membrane potential (ΔΨm) estimated using 5,5′,6,6′-tetrachloro 1,1′3,3′-tetraethylbenzimid azolocarbocyanine iodide. Expression of mitochondrial and antioxidant genes was determined by real-time polymerase chain reaction. RPE cells show greater sensitivity to oxidative stress, reduction in expression of mitochondrial heat shock protein 70, uncoupling protein 2, and superoxide dismutase 3, and greater expression of superoxide dismutase 2 levels with increased chronological age. Changes in mitochondrial number, size, shape, matrix density, cristae architecture, and membrane integrity were more prominent in samples obtained from >60 years old compared to midage and younger donors. These mitochondria abnormalities correlated with lower ATP levels, reduced ΔΨm, decreased [Ca 2+ ] c , and increased sequestration of [Ca 2+ ] m in cells with advanced aging. Our study provides evidence for mitochondrial decay, bioenergetic deficiency, weakened antioxidant defenses, and increased sensitivity of RPE cells to oxidative stress with advanced aging. Our findings suggest that with increased severity of mitochondrial decay and oxidative stress, RPE function may be altered in some individuals in a way that makes the retina more susceptible to age-related injury.

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DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?

Cited by 294 publications

References 123 publications

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

Telomere length is correlated with mitochondrial DNA copy number in intestinal, but not diffuse, gastric cancer

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

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