DNA damage and aging

Karanjawala, Zarir E.; Lieber, Michael R.

doi:10.1016/j.mad.2004.04.003

Cited by 62 publications

(12 citation statements)

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“…It can also lead to translocations and telomere fusion, hallmarks of tumor cells [19]. The progressive accumulation of DNA damage with each sequential cell cycle has been considered to be the primary cause of cell aging and senescence [20]. However, the notion that persistent stimulation of mTOR-driven pathways (rather than the ROS-induced DNA damage) is the major mechanism responsible for aging appears to have more merit [21-27].…”

Section: Introductionmentioning

confidence: 99%

Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling

Halicka

Zhao

et al. 2011

Aging

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We have shown before that constitutive DNA damage signaling represented by H2AX-Ser139 phosphorylation and ATM activation in untreated normal and tumor cells is a reporter of the persistent DNA replication stress induced by endogenous oxidants, the by-products of aerobic respiration. In the present study we observed that exposure of normal mitogenically stimulated lymphocytes or tumor cell lines A549, TK6 and A431 to metformin, the specific activator of 5'AMP-activated protein kinase (AMPK) and an inhibitor of mTOR signaling, resulted in attenuation of constitutive H2AX phosphorylation and ATM activation. The effects were metformin-concentration dependent and seen even at the pharmacologically pertinent 0.1 mM drug concentration. The data also show that intracellular levels of endogenous reactive oxidants able to oxidize 2',7'-dihydro-dichlorofluorescein diacetate was reduced in metformin-treated cells. Since persistent constitutive DNA replication stress, particularly when paralleled by mTOR signaling, is considered to be the major cause of aging, the present findings are consistent with the notion that metformin, by reducing both DNA replication stress and mTOR-signaling, slows down aging and/or cell senescence processes.

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Section: Introductionmentioning

confidence: 99%

Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling

Halicka

Zhao

et al. 2011

Aging

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“…Mice deficient in proteins involved in DNA damage sensing and repair exhibit severe deficiencies in these pathways leading to accelerated aging and oncogenic transformation [4]. Many progeria (premature aging) syndromes in humans are caused by mutations in genes encoding proteins involved in DNA repair and are associated with increased incidence of cancer [5,6]. …”

Section: Introductionmentioning

confidence: 99%

Telomere-dependent and telomere-independent origins of endogenous DNA damage in tumor cells

Nakamura

Redon²,

Bonner³

et al. 2009

Aging

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Human tumors and cultured cells contain elevated levels of endogenous DNA damage resulting from telomere dysfunction, replication and transcription errors, reactive oxygen species, and genome instability. However, the contribution of telomere-associated versus telomere-independent endogenous DNA lesions to this damage has never been examined. In this study, we characterized the relative amounts of these two types of DNA damage in five tumor cell lines by noting whether γ-H2AX foci, generally considered to mark DNA double-strand breaks (DSBs), were on chromosome arms or at chromosome ends. We found that while the numbers of non-telomeric DSBs were remarkably similar in these cultures, considerable variation was detected in the level of telomeric damage. The distinct heterogeneity in the numbers of γ-H2AX foci in these tumor cell lines was found to be due to foci associated with uncapped telomeres, and the amount of total telomeric damage also appeared to inversely correlate with the telomerase activity present in these cells. These results indicate that damaged telomeres are the major factor accounting for the variability in the amount of DNA DSB damage in tumor cells. This characterization of DNA damage in tumor cells helps clarify the contribution of non-telomeric DSBs and damaged telomeres to major genomic alterations.

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“…The damage manifests as oxidation of DNA bases with a prevalence of guanine adducts such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG)], fragmentation of base rings, sugar modification, DNA and protein crosslinking, and induction of DNA strand breaks (DSBs) (2,15,16). Repair of DSBs can be error prone leading to deletion of base pairs and producing defects that result in translocations and chromosomal instability (3,4,17,18). Alterations in molecular structure of DNA accumulating with time are important factors in promoting aging, cellular senescence, and predisposing to cancer (1–6,19–21).…”

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confidence: 99%

Induction of DNA damage signaling by oxidative stress in relation to DNA replication as detected using “click chemistry”

Zhao¹,

Dobrucki²,

Rybak³

et al. 2011

Cytometry Pt A

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Induction of DNA damage by oxidants such as H2O2 activates the complex network of DNA damage response (DDR) pathways present in cells to initiate DNA repair, halt cell cycle progression, and prepare an apoptotic reaction. We have previously reported that activation of Ataxia Telangiectasia Mutated protein kinase (ATM) and induction of γH2AX are among the early events of the DDR induced by exposure of cells to H2O2, and in human pulmonary carcinoma A549 cells, both events were expressed predominantly during S-phase. This study was designed to further explore a correlation between these events and DNA replication. Toward this end, we utilized 5-ethynyl-2′deoxyuridine (EdU) and the “click chemistry” approach to label DNA during replication, followed by exposure of A549 cells to H2O2. Multiparameter laser scanning cytometric analysis of these cells made it possible to identify DNA replicating cells and directly correlate H2O2-induced ATM activation and induction of γH2AX with DNA replication on a cell by cell basis. After pulse-labeling with EdU and exposure to H2O2, confocal microscopy was also used to examine the localization of DNA replication sites (“replication factories”) versus the H2AX phosphorylation sites (γH2AX foci) in nuclear chromatin in an attempt to observe the absence or presence of colocalization. The data indicate a close association between DNA replication and H2AX phosphorylation in A549 cells, suggesting that these DNA damage response events may be triggered by stalled replication forks and perhaps also by induction of DNA double-strand breaks at the primary DNA lesions induced by H2O2

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DNA damage and aging

Cited by 62 publications

References 0 publications

Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling

Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling

Telomere-dependent and telomere-independent origins of endogenous DNA damage in tumor cells

Induction of DNA damage signaling by oxidative stress in relation to DNA replication as detected using “click chemistry”

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