Chemical screening identifies ATM as a target for alleviating senescence

Kang, Hyeran; Park, Taezoon; Choi, Kobong; Kim, Yongsub; Choi, Hyung Yun; Jung, Chul Won; Lee, Young‐Sam; Park, Sang Chul

doi:10.1038/nchembio.2342

Cited by 127 publications

(81 citation statements)

References 59 publications

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“…Treatment with KU‐60019 decreased SAβgal activity in senescent fibroblasts, removed dysfunctional mitochondria and resulted in metabolic reprogramming. KU‐60019 therapy accelerated cutaneous wound healing in aged mice, and inhibition of ATM activity also attenuated senescence (Kang et al , ); KU‐60019 is therefore a promising candidate target for treatment of age‐related diseases.…”

Section: Introductionmentioning

confidence: 99%

Targeting senescent cells in translational medicine

et al. 2019

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Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age‐related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.

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Section: Introductionmentioning

confidence: 99%

Targeting senescent cells in translational medicine

et al. 2019

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“…DNA-PKcs and ATM also phosphorylate each other (Chen et al, 2007), with DNA-PKcs serving as a negative regulator of ATM (Finzel et al, 2016;Zhou et al, 2017). This negative feedback may explain the seemingly inconsistent observations that while ATM inhibitors block γH2AX foci formation (Burma et al, 2001) and suppress checkpoint arrest and cellular senescence (Kang et al, 2017), DNA-PK inhibitors delay γH2AX foci resolution and promote checkpoint arrest and cellular senescence (Azad et al, 2011;Ciszewski et al, 2014;Sunada et al, 2016;Zhao et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Repair-independent functions of DNA-PKcs protect irradiated cells from mitotic slippage and accelerated senescence

Liu

Efimova

Ramamurthy

et al. 2019

Journal of Cell Science

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The binding of DNA-dependent protein kinase catalytic subunit (DNA-PKcs, also known as PRKDC) to Ku proteins at DNA doublestrand breaks (DSBs) has long been considered essential for nonhomologous end joining (NHEJ) repair, providing a rationale for use of DNA-PKcs inhibitors as cancer therapeutics. Given lagging clinical translation, we reexamined mechanisms and observed instead that DSB repair can proceed independently of DNA-PKcs. While repair of radiation-induced DSBs was blocked in cells expressing shRNAs targeting Ku proteins or other NHEJ core factors, DSBs were repaired on schedule despite targeting DNA-PKcs. Although we failed to observe a DSB repair defect, the γH2AX foci that formed at sites of DNA damage persisted indefinitely after irradiation, leading to cytokinesis failure and accumulation of binucleated cells. Following this mitotic slippage, cells with decreased DNA-PKcs underwent accelerated cellular senescence. We identified downregulation of ataxia-telangiectasia mutated kinase (ATM) as the critical role of DNA-PKcs in recovery from DNA damage, insofar as targeting ATM restored γH2AX foci resolution and cytokinesis. Considering the lack of direct impact on DSB repair and emerging links between senescence and resistance to cancer therapy, these results suggest reassessing DNA-PKcs as a target for cancer treatment.

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“…To dissect the hierarchical relationship between ATM and SUVH2 in DSB‐triggered leaf senescence, we utilized KU, a specific inhibitor of the ATM kinase in plants as well as in animals (Montane & Menand, 2013; Kang et al , 2017). Treatment with 10 µM KU alone caused no evident change in the F v / F m ratio in Col‐0, atm , or SUVH2ox leaves (Fig.…”

Section: Resultsmentioning

confidence: 99%

ATM suppresses leaf senescence triggered by DNA double‐strand break through epigenetic control of senescence‐associated genes in Arabidopsis

Kim

Lyu

et al. 2020

New Phytologist

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Summary All living organisms are unavoidably exposed to various endogenous and environmental stresses that trigger potentially fatal DNA damage, including double‐strand breaks (DSBs). Although a growing body of evidence indicates that DNA damage is one of the prime drivers of aging in animals, little is known regarding the importance of DNA damage and its repair on lifespan control in plants. We found that the level of DSBs increases but DNA repair efficiency decreases as Arabidopsis leaves age. Generation of DSBs by inducible expression of I‐PpoI leads to premature senescence phenotypes. We examined the senescence phenotypes in the loss‐of‐function mutants for 13 key components of the DNA repair pathway and found that deficiency in ATAXIA TELANGIECTASIA MUTATED (ATM), the chief transducer of the DSB signal, results in premature senescence in Arabidopsis. ATM represses DSB‐induced expression of senescence‐associated genes, including the genes encoding the WRKY and NAC transcription factors, central components of the leaf senescence process, via modulation of histone lysine methylation. Our work highlights the significance of ATM in the control of leaf senescence and has significant implications for the conservation of aging mechanisms in animals and plants.

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Chemical screening identifies ATM as a target for alleviating senescence

Cited by 127 publications

References 59 publications

Targeting senescent cells in translational medicine

Targeting senescent cells in translational medicine

Repair-independent functions of DNA-PKcs protect irradiated cells from mitotic slippage and accelerated senescence

ATM suppresses leaf senescence triggered by DNA double‐strand break through epigenetic control of senescence‐associated genes in Arabidopsis

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