Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase

Salim Abdisalaam, Souparno Bhattacharya, Shibani Mukherjee, Debapriya Sinha, Kalayarasan Srinivasan, Mingrui Zhu, Esra A. Akbay, Hesham A. Sadek, Jerry W. Shay, Aroumougame Asaithamby

Research output: Contribution to journalArticle

Abstract

Defective DNA damage response (DDR) signaling is a common mechanism that initiates and maintains the cellular senescence phenotype. Dysfunctional telomeres activate DDR signaling, genomic instability, and cellular senescence, but the links among these events remains unclear. Here, using an array of biochemical and imaging techniques, including a highly regulatable CRISPR/Cas9 strategy to induce DNA double strand breaks specifically in the telomeres, ChIP, telomere immunofluorescence, fluorescence in situ hybridization (FISH), micronuclei imaging, and the telomere shortest length assay (TeSLA), we show that chromosome mis-segregation due to imperfect DDR signaling in response to dysfunctional telomeres creates a preponderance of chromatin fragments in the cytosol, which leads to a premature senescence phenotype. We found that this phenomenon is caused not by telomere shortening, but by cyclic GMP-AMP synthase (cGAS) recognizing cytosolic chromatin fragments and then activating the stimulator of interferon genes (STING) cytosolic DNA-sensing pathway and downstream interferon signaling. Significantly, genetic and pharmacological manipulation of cGAS not only attenuated immune signaling, but also prevented premature cellular senescence in response to dysfunctional telomeres. The findings of our study uncover a cellular intrinsic mechanism involving the cGAS-mediated cytosolic self-DNA-sensing pathway that initiates premature senescence independently of telomere shortening.

Original languageEnglish (US)
Pages (from-to)11144-11160
Number of pages17
JournalThe Journal of biological chemistry
Volume295
Issue number32
DOIs
StatePublished - Aug 7 2020

Keywords

  • CRISPR/Cas
  • DNA damage
  • DNA damage response
  • chromatin
  • cyclic GMP-AMP synthase (cGAS)
  • genome maintenance
  • micronuclei
  • senescence
  • telomere

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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