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

Robinson, Andria Rasile; Yousefzadeh, Matthew J.; Rozgaja, Tania A.; Wang, Jin; Li, Xuesen; Tilstra, Jeremy S.; Feldman, Chelsea H.; Gregg, Siobhán Q.; Johnson, Caroline H.; Skoda, Erin M.; Frantz, Marie‐Céline; Bell-Temin, Harris; Pope-Varsalona, Hannah; Gurkar, Aditi U.; Nasto, Luigi Aurelio; Robinson, Renã A. S.; Fuhrmann-Stroissnigg, Heike; Czerwińska, Jolanta; McGowan, Sara J.; Cantú‐Medellín, Nadiezhda; Harris, Jamie B.; Maniar, Salony; Ross, Mark A.; Trussoni, Christy E.; LaRusso, Nicholas F.; Cifuentes-Pagano, Eugenia; Pagano, Patrick J.; Tudek, Barbara; Vo, Nam; Rigatti, Lora H.; Opresko, Patricia L.; Stolz, Donna B.; Watkins, Simon C.; Burd, Christin E.; Croix, Claudette M. St.; Siuzdak, Gary; Yates, Nathan A.; Robbins, Paul D.; Wang, Yinsheng; Wipf, Peter; Kelley, Eric E.; Niedernhofer, Laura J.

doi:10.1016/j.redox.2018.04.007

Cited by 118 publications

(96 citation statements)

References 102 publications

(127 reference statements)

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“…Taken together, our data demonstrate that Ercc1 − /∆ mice share a pattern of cellular senescence that is consistent and commensurate with that observed in aged WT mice. The DNA repair‐deficient Ercc1 − /∆ mice accumulate endogenous DNA damage faster than WT mice (Robinson, ; Wang et al, ), and we now show that this corresponds with the accelerated accumulation of senescent cells. This supports the conclusions that spontaneous, endogenous DNA damage drives cellular senescence in vivo with natural aging and that the Ercc1 − /∆ mice truly age in an accelerated manner.…”

Section: Discussionsupporting

confidence: 69%

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

et al. 2020

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Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1−/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1−/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1−/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1−/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.

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Section: Discussionsupporting

confidence: 69%

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

et al. 2020

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“…Ercc1 −/Δ mice are a model for human Cockayne and COF syndromes, which are rare progeroid syndromes with extremely short lifespans (Gregg et al, 2011;Vermeij, Dollé, et al, 2016). Increases in both cellular senescence and apoptosis in Ercc1 −/Δ mice have been reported (Niedernhofer et al, 2006;Robinson et al, 2018;Takayama et al, 2014;Tilstra et al, 2012;Weeda et al, 1997). These two processes are partly interconnected by common molecular pathways (Childs et al, 2014), but how they interact is not clear.…”

Section: Senescent Cells Are Generally Resistant To Apoptosis Often Duementioning

confidence: 99%

Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin

et al. 2019

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ERCC1 (excision repair cross complementing‐group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross‐link repair. Ercc1−/Δ mice, carrying one null and one hypomorphic Ercc1 allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. Ercc1−/Δ mice display combined features of human progeroid and cancer‐prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of Ercc1−/Δ mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1−/Δ mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1−/Δ mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence‐associated secretory phenotype) factors. Cellular senescence induced by ERCC1 deficiency was dependent on activity of the p53 tumor‐suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring ERCC1‐deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in Ercc1−/Δ mouse skin, where the apoptotic cells are localized, compared to age‐matched wild‐type skin, possibly due to the apoptosis of stem cells. These data suggest that ERCC1‐depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health‐ or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.

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“…In addition, suppression of the GH/IGF1 axis is also observed in the mouse model defective for both Csb and Xpa functions, whose phenotype largely mimics the CS clinical features . Of note, a recent study in the Ercc1 Δ /− mice has shown that these animals accumulate oxidative DNA damage more rapidly than age‐matched wild‐type mice and that oxidative stress appears to be due, at least in part, to mitochondrial‐derived ROS …”

Section: Molecular Basis Of Overlap Syndromesmentioning

confidence: 99%

Heterogeneity and overlaps in nucleotide excision repair disorders

2019

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Nucleotide excision repair (NER) is an essential DNA repair pathway devoted to the removal of bulky lesions such as photoproducts induced by the ultraviolet (UV) component of solar radiation. Deficiencies in NER typically result in a group of heterogeneous distinct disorders ranging from the mild UV sensitive syndrome to the cancer-prone xeroderma pigmentosum and the neurodevelopmental/progeroid conditions trichothiodystrophy, Cockayne syndrome and cerebro-oculo-facio-skeletalsyndrome. A complicated genetic scenario underlines these disorders with the same gene linked to different clinical entities as well as different genes associated with the same disease. Overlap syndromes with combined hallmark features of different NER disorders can occur and sporadic presentations showing extra features of the hematological disorder Fanconi Anemia or neurological manifestations mimicking Hungtinton disease-like syndromes have been described. Here, we discuss the multiple functions of the five major pleiotropic NER genes (ERCC3/XPB, ERCC2/XPD, ERCC5/ XPG, ERCC1 and ERCC4/XPF) and their relevance in phenotypic complexity. We provide an update of mutational spectra and examine genotype-phenotype relationships.Finally, the molecular defects that could explain the puzzling overlap syndromes are discussed. K E Y W O R D Sgenotype-phenotype relationships, NER disorders, nucleotide excision repair (NER), overlap syndromes

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

Cited by 118 publications

References 102 publications

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin

Heterogeneity and overlaps in nucleotide excision repair disorders

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