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The caspase-activated DNase promotes cellular senescence.
Haimovici, Aladin; Rupp, Valentin; Amer, Tarek; Moeed, Abdul; Weber, Arnim; Häcker, Georg.
Afiliación
  • Haimovici A; Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany. aladin.haimovici@uniklinik-freiburg.de.
  • Rupp V; Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • Amer T; Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • Moeed A; Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • Weber A; Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • Häcker G; Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany. georg.haecker@uniklinik-freiburg.de.
EMBO J ; 43(16): 3523-3544, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38977850
ABSTRACT
Cellular senescence is a response to many stressful insults. DNA damage is a consistent feature of senescent cells, but in many cases its source remains unknown. Here, we identify the cellular endonuclease caspase-activated DNase (CAD) as a critical factor in the initiation of senescence. During apoptosis, CAD is activated by caspases and cleaves the genomic DNA of the dying cell. The CAD DNase is also activated by sub-lethal signals in the apoptotic pathway, causing DNA damage in the absence of cell death. We show that sub-lethal signals in the mitochondrial apoptotic pathway induce CAD-dependent senescence. Inducers of cellular senescence, such as oncogenic RAS, type-I interferon, and doxorubicin treatment, also depend on CAD presence for senescence induction. By directly activating CAD experimentally, we demonstrate that its activity is sufficient to induce senescence in human cells. We further investigate the contribution of CAD to senescence in vivo and find substantially reduced signs of senescence in organs of ageing CAD-deficient mice. Our results show that CAD-induced DNA damage in response to various stimuli is an essential contributor to cellular senescence.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Daño del ADN / Senescencia Celular Límite: Animals / Humans Idioma: En Revista: EMBO J Año: 2024 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Daño del ADN / Senescencia Celular Límite: Animals / Humans Idioma: En Revista: EMBO J Año: 2024 Tipo del documento: Article País de afiliación: Alemania