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Chemical screening identifies ATM as a target for alleviating senescence
- Chemical screening identifies ATM as a target for alleviating senescence
- Kang, Hyun Tae; Park, Joon Tae; Choi, Kobong; Kim, Yongsub; Choi, Hyo Jei Claudia; Jung, Chul Won; Lee, Young-Sam; Park, Sang Chul
- DGIST Authors
- Lee, Young-Sam
- Issue Date
- Nature Chemical Biology, 13(6), 616-+
- Article Type
- Acidification; Activation; Autophagy; Disease; Epithelial Cells; Kinase; Lifespan; Lysosomal Ph; Mitochondria; Yeast Vacuolar Atpase
- Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V-1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1. Attenuation of ATM activity restored the dimerization, thus consequently facilitating assembly of the V-1 and V-0 domains with concomitant reacidification of the lysosome. In turn, this reacidification induced the functional recovery of the lysosome/autophagy system and was coupled with mitochondrial functional recovery and metabolic reprogramming. Together, our data reveal a new mechanism through which senescence is controlled by the lysosomal-mitochondrial axis, whose function is modulated by the fine-tuning of ATM activity.
- NATURE PUBLISHING GROUP
- Related Researcher
Lab of genome maintenance
DNA replication and repair; Restoration of cellular senescence; Structural and functional relationship of proteins
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- Department of New BiologyLab of Genome Maintenance1. Journal Articles
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