Cited 2 time in webofscience Cited 1 time in scopus

Chemical screening identifies ATM as a target for alleviating senescence

Title
Chemical screening identifies ATM as a target for alleviating senescence
Authors
Kang, Hyun TaePark, Joon TaeChoi, KobongKim, YongsubChoi, Hyo Jei ClaudiaJung, Chul WonLee, Young-SamPark, Sang Chul
DGIST Authors
Lee, Young-Sam; Park, Sang Chul
Issue Date
2017-06
Citation
Nature Chemical Biology, 13(6), 616-+
Type
Article
Article Type
Article
Keywords
AcidificationActivationAutophagyDiseaseEpithelial CellsKinaseLifespanLysosomal PhMitochondriaYeast Vacuolar Atpase
ISSN
1552-4450
Abstract
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.
URI
http://hdl.handle.net/20.500.11750/4162
DOI
10.1038/nchembio.2342
Publisher
NATURE PUBLISHING GROUP
Related Researcher
  • Author Lee, Young Sam Lab of genome maintenance
  • Research Interests DNA replication and repair; Restoration of cellular senescence; Structural and functional relationship of proteins
Files:
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Collection:
New BiologyETC1. Journal Articles
New BiologyETC1. Journal Articles


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