Probing the Telomere Damage Response

Rai, Rekha; Chang, Sandy

doi:10.1007/978-1-4939-6892-3_13

Cited by 5 publications

(3 citation statements)

References 10 publications

(9 reference statements)

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“…Notably, sgTERC‐3 and sgTERC‐8 cells were more susceptible to SARS‐CoV‐2 pseudovirus infection than wild‐type Calu‐3 cells and Caffeine treatment inhibited the effect (Figure 3e ). Moreover, TPP1ΔRD and POT1ΔOB, two mutants of shelterin complex which is essential for protecting telomere ends, were transiently transfected into Caco‐2 cells to induce telomere uncapping and telomere damage (Figure S5 a; Rai & Chang, 2017 ). Expression of ACE2 and c‐Jun was increased in cells transfected with the mutants and Caffeine inhibited increasing of ACE2 (Figure S5 b,c).…”

Section: Resultsmentioning

confidence: 99%

DNA damage contributes to age‐associated differences in SARS‐CoV‐2 infection

Jin¹,

Niu

et al. 2022

Aging Cell

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Coronavirus disease 2019 , caused by coronavirus SARS-CoV-2, is known to disproportionately affect older individuals 1,2 . How aging processes affect the disease progression remains largely unknown. Here we found that DNA damage, one of the major causes of aging 3 , promoted susceptibility to SARS-CoV-2 infection in cells and intestinal organoids. SARS-CoV-2 entry was facilitated by DNA damage caused by telomere attrition or extrinsic genotoxic stress and hampered by inhibition of DNA damage response (DDR). Mechanistic analysis revealed that DDR increased expression of ACE2, the receptor of SARS-CoV-2, by activation of transcription factor c-Jun in vitro and in vivo. Expression of ACE2 was elevated in the older tissues and positively correlated with γH2Ax and phosphorylated c-Jun (p-c-Jun). Finally, targeting DNA damage by increasing the DNA repair capacity, alleviated cell susceptibility to SARS-CoV-2. Our data provide insights into the age-associated differences in SARS-CoV-2 infection and a novel target for anti-viral intervention. SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, primarily infiltrates cells through the receptor ACE2. This membrane protein is also the receptor of SARS-CoV which led to an outbreak in 2003 4 . COVID-19 disproportionately affects older individuals, who are more likely to develop severe symptoms and experience higher mortality 1,2 . Many possible reasons underlie these age-associated differences, including different cell susceptibility to viruses and different immune response and capacity against viral infection 5,6 . An inherent aspect of the aging process is the accumulation of DNA damage over time, which can be detected by γH2Ax staining 3,7,8 . Although most DNA lesions arising from extrinsic or intrinsic damage are quickly repaired, a very small number of highly toxic lesions can persist and accumulate, especially DNA damage occurring at telomeres, which is caused by telomere attrition upon cell division or genotoxic stress 9,10 . Another reason for the accumulation of DNA damage is the decline in DNA repair capacity arising from changes in the expression or activity of molecules involved in DNA repair 11 . Moreover, DNA damage was one of the primary causes of aging [12][13][14] . Numerous premature aging diseases, such as Werner syndrome and Bloom syndrome, are the consequences of

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Section: Resultsmentioning

confidence: 99%

DNA damage contributes to age‐associated differences in SARS‐CoV‐2 infection

Jin¹,

Niu

et al. 2022

Aging Cell

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“…Importantly, ERCC1-XPF-deficient human and murine cells do not show accelerated telomere attrition [60] . To confirm the absence of telomere dysfunction, we measured telomere damage-induced foci [61] in Ercc1 -/- and WT mouse embryonic fibroblasts (Supplemental Fig. 2 ).…”

Section: Resultsmentioning

confidence: 99%

Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging

Robinson¹,

et al. 2018

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Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/∆ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/∆ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/∆ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/∆ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1-/∆ and aged WT mice. Chronic treatment of Ercc1-/∆ mice with the mitochondrial-targeted radical scavenger XJB-5–131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline.

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“…Indirect immunofluorescence (IF) combined with fluorescence in situ hybridization (FISH) analysis was performed as described (Rai & Chang, 2011) with some modifications. Briefly, cells grown on coverslips were fixed for 15 min in 2% paraformaldehyde/2% sucrose at RT, followed by permeabilization for 10 min in 1× PBS/ 0.5% Nonidet-P40 at RT.…”

Section: Immuno-fish Assaymentioning

confidence: 99%

ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization

et al. 2019

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Loss of the histone H3.3‐specific chaperone component ATRX or its partner DAXX frequently occurs in human cancers that employ alternative lengthening of telomeres (ALT) for chromosomal end protection, yet the underlying mechanism remains unclear. Here, we report that ATRX/DAXX does not serve as an immediate repressive switch for ALT. Instead, ATRX or DAXX depletion gradually induces telomere DNA replication dysfunction that activates not only homology‐directed DNA repair responses but also cell cycle checkpoint control. Mechanistically, we demonstrate that this process is contingent on ATRX/DAXX histone chaperone function, independently of telomere length. Combined ATAC‐seq and telomere chromatin immunoprecipitation studies reveal that ATRX loss provokes progressive telomere decondensation that culminates in the inception of persistent telomere replication dysfunction. We further show that endogenous telomerase activity cannot overcome telomere dysfunction induced by ATRX loss, leaving telomere repair‐based ALT as the only viable mechanism for telomere maintenance during immortalization. Together, these findings implicate ALT activation as an adaptive response to ATRX/DAXX loss‐induced telomere replication dysfunction.

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Probing the Telomere Damage Response

Cited by 5 publications

References 10 publications

DNA damage contributes to age‐associated differences in SARS‐CoV‐2 infection

DNA damage contributes to age‐associated differences in SARS‐CoV‐2 infection

Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging

ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization

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