ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging.

Debora Colangelo, Emilio Corbo, Enrico Pola, J Zhao, L Zhang, A Lu, Y Han, C Bukata, A Scibetta, MJ Yousefzadeh, 1 Li, AU Gurkar, SJ McGowan, L Angelini, R O'Kelly, H Li, T Sano, H Nick, SPS Pilla, WC LadigesN Vo, J Huard, LJ Niedernhofer, PD. Robbins

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11 Citazioni (Scopus)


NF-κB is a transcription factor activated in response to inflammatory, genotoxic and oxidative stress and important for driving senescence and aging. Ataxia-telangiectasia mutated (ATM) kinase, a core component of DNA damage response signaling, activates NF-κB in response to genotoxic and oxidative stress via post-translational modifications. Here we demonstrate that ATM is activated in senescent cells in culture and murine tissues from Ercc1-deficient mouse models of accelerated aging, as well as naturally aged mice. Genetic and pharmacologic inhibition of ATM reduced activation of NF-κB and markers of senescence and the senescence-associated secretory phenotype (SASP) in senescent Ercc1-/- MEFs. Ercc1-/Δ mice heterozygous for Atm have reduced NF-κB activity and cellular senescence, improved function of muscle-derived stem/progenetor cells (MDSPCs) and extended healthspan with reduced age-related pathology especially age-related bone and intervertebral disc pathologies. In addition, treatment of Ercc1-/∆ mice with the ATM inhibitor KU-55933 suppressed markers of senescence and SASP. Taken together, these results demonstrate that the ATM kinase is a major mediator of DNA damage-induced, NF-κB-mediated cellular senescence, stem cell dysfunction and aging and thus represents a therapeutic target to slow the progression of aging.
Lingua originaleEnglish
pagine (da-a)4688-4710
Numero di pagine23
Stato di pubblicazionePubblicato - 2020


  • ATM
  • DNA damage response
  • NF-κB
  • aging
  • cellular senescence


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