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

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. 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. Senescence is an intrinsic cellular response that induces irreversible cell-cycle arrest. Although there are many triggers for cellular senescence, defective DNA damage response (DDR) signaling is thought to be one of the common mechanisms that induces and maintains the senescence phenotype (1Fumagalli M. d'Adda di Fagagna F. SASPense and DDRama in cancer and ageing.Nat. Cell Biol. 2009; 11 (19648977): 921-92310.1038/ncb0809-921Crossref PubMed Scopus (88) Google Scholar). DDR signaling is often activated by telomere dysfunction due to loss of or defects in telomere-binding proteins, endonuclease (Isce1)-based introduction of double strand breaks (DSBs) in the subtelomeric regions (2Miller D. Reynolds G.E. Mejia R. Stark J.M. Murnane J.P. Subtelomeric regions in mammalian cells are deficient in DNA double-strand break repair.DNA Repair. 2011; 10 (21466975): 536-54410.1016/j.dnarep.2011.03.001Crossref PubMed Scopus (33) Google Scholar), telomeric DSBs induced by TRF1 fusing with the Fokl enzyme (3Cho N.W. Dilley R.L. Lampson M.A. Greenberg R.A. Interchromosomal homology searches drive directional ALT telomere movement and synapsis.Cell. 2014; 159 (25259924): 108-12110.1016/j.cell.2014.08.030Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar), telomeric damage induced by laser microirradiation (4Silva B.A. Stambaugh J.R. Yokomori K. Shah J.V. Berns M.W. DNA damage to a single chromosome end delays anaphase onset.J. Biol. 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Chromothripsis and kataegis induced by telomere crisis.Cell. 2015; 163 (26687355): 1641-165410.1016/j.cell.2015.11.054Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). Cellular senescence due to replicative exhaustion, i.e. telomere shortening, has been studied extensively (11Harley C.B. Futcher A.B. Greider C.W. Telomeres shorten during ageing of human fibroblasts.Nature. 1990; 345 (2342578): 458-46010.1038/345458a0Crossref PubMed Scopus (4608) Google Scholar). However, the signaling cascade responsible for initiating cellular senescence independently of telomere shortening, but in response to telomere dysfunction, remains incompletely characterized. Recent findings have provided mechanistic insights into how genomic instability due to defective DDR signaling triggers immune signaling. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, detects cytosolic DNA as a danger-associated and initiates immune L. J. F. Cyclic GMP-AMP synthase is a cytosolic DNA that the interferon PubMed Scopus Google Scholar). that the due to DDR signaling, of chromatin fragments in the of micronuclei and the subsequent of the cGAS activation K. K. C. S. M. K. N. A. B. of triggers of micronuclei by PubMed Scopus Google Scholar, K. J. J. Lan Y. Y. Xu C. Xu M. T. chromatin triggers in senescence and PubMed Scopus Google Scholar, S. B. K. A. J. L. A. immune of cytosolic chromatin fragments through cGAS Cell Biol. PubMed Scopus Google Scholar, J. Greenberg R.A. progression DNA damage PubMed Scopus Google Scholar, A. N. A. M. N. T. of micronuclei links genome instability to PubMed Scopus Google Scholar, J. cGAS is for cellular PubMed Scopus Google Scholar). a result of cGAS activation in response to cytosolic chromatin cells can to or irreversible cell i.e. cellular senescence P.J. A.S. J.M. of human cGAS a of in 3 Full Text Full Text PDF PubMed Scopus Google Scholar, P.J. cGAS DNA Full Text Full Text PDF PubMed Scopus Google Scholar, F. T. de Mann A. M. G. V. mechanism of cytosolic DNA by PubMed Scopus Google Scholar, C. G. J. A.B. Li Cyclic GMP-AMP synthase is activated by Full Text Full Text PDF PubMed Scopus Google Scholar, J. F. Xu L. The cytosolic DNA cGAS an with DNA and in the activation 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). However, is not DDR signaling activated in response to telomere damage can also activate the cytosolic DNA-sensing pathway and cellular this we have not only a to induce DSBs specifically in telomeric but we also that cGAS-mediated immune signaling is activated in response to cytosolic chromatin fragments by dysfunctional telomeres. we show that cells that fused in response to dysfunctional telomeres to which leads to the of chromatin fragments in the the cGAS to chromatin fragments DSBs and immune signaling, which often leads to premature cGAS cytosolic chromatin fragments in response to dysfunctional telomeres, and that triggers premature senescence independently of telomere shortening. induce DSBs specifically in telomeric we a telomere CRISPR/Cas9 genome M. K. M. DNA endonuclease in 2012; PubMed Scopus Google Scholar). This of a and a The a telomere with B. B.A. J. Li J. B. imaging of genomic in human cells by an Full Text Full Text PDF PubMed Scopus Google Scholar). This has been to study telomere in human cells B. B.A. J. Li J. B. imaging of genomic in human cells by an Full Text Full Text PDF PubMed Scopus Google Scholar). is an endonuclease with one for strand of the M. K. M. DNA endonuclease in 2012; PubMed Scopus Google Scholar). The the to telomeric induce DSBs the telomeric we fused to or to the of a the is and in the and to in cells using Full Text Full Text PDF PubMed Scopus Google Scholar). is by a to cells with and in the of and We a of a of with and a telomere at and we a and Although the that we have for telomeric DNA in this study has been we the of telomeric by this we the of by using and this we induced DSBs in the by cells with and for with and the chromatin using F. S. Y. S. J. A. for in DNA 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). we genomic DNA and then using that of the the telomeric i.e. at the end of the chromosome these that a of DSBs induced by are the telomeric that telomeric DSBs are to DSBs (6Fumagalli M. Rossiello F. Clerici M. Barozzi S. Cittaro D. Kaplunov J.M. Bucci G. Dobreva M. Matti V. Beausejour C.M. Herbig U. Longhese M.P. d'Adda di Fagagna F. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation.Nat. Cell Biol. 2012; 14 (22426077): 355-36510.1038/ncb2466Crossref PubMed Scopus (526) Google Scholar). to DSBs induced by our we cells with for and then the cells with and at to a study with telomere damage induced by TRF1 (5Sun L. Tan R. Xu J. LaFace J. Gao Y. Xiao Y. Attar M. Neumann C. Li G.M. Su B. Liu Y. Nakajima S. Levine A.S. Lan L. Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death.Nucleic Acids Res. 2015; 43: 6334-634710.1093/nar/gkv598Crossref PubMed Scopus (53) Google Scholar), we found the DSBs in the telomeric at the We that of these telomeric DNA DSBs the of these we also that with DSBs as a result of and A. of DNA double-strand breaks and of DNA Biol. 2014; PubMed Scopus Google Scholar). our a of telomeric DSBs but that the cells to DSBs This has an of which cells can D. J. A. L. A. S. T. M. Cell Biol. PubMed Scopus Google Scholar, G.E. G. in of breaks in Res. PubMed Scopus Google Scholar, A. B. DNA induce chromosome in human 2011; PubMed Scopus Google Scholar). We found that the of telomeric DSBs the for we the and of the We found that of and in activated in response to to DSBs by ionizing radiation of the the 3 that cells with only in and through activation in response to telomeric DSBs is and to cells that in that the of dysfunctional telomeres causes fusion of B. A. de Lange T. human telomeres Full Text Full Text PDF PubMed Scopus Google Scholar). is that the progression of cells to causes mis-segregation of fused in which in the of chromosome of of chromosome specifically in cells with telomeric DSBs in cells the of fused we the of micronuclei the of telomeric We found that the of cells in cells with telomeric DSBs in cells we of micronuclei at in at the the DDR is in response to telomeric cells to to with damage or fused which in the of micronuclei as a for genomic instability and a for DDR micronuclei can cGAS and activate the cytosolic DNA-sensing pathway K. J. J. Lan Y. Y. Xu C. Xu M. 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We found that the of cells 10 the of with in cells we the of cells by with for We that the of cells in cells in cells we and of the senescence by S. J. A. J. G. of to replicative senescence of human Cell Res. PubMed Scopus Google Scholar, Li J. K. J. J. Liu R. Xu A. T. J. Li Y. L. D. a cell as a of human 2015; PubMed Scopus Google Scholar). We found of and of the of that telomere is a of cellular senescence, we telomere length in cells with telomeric DNA by the (TeSLA), as N. J. G. for the of the shortest telomeres in cells and Commun. PubMed Scopus Google Scholar). We found that the telomere not and and we that the of telomeres and but the We to that the telomeric for and the of of fused in telomeric DNA DSBs can have the of telomere in these that DSBs in the telomeric DNA and in signaling, which in cellular we to the cGAS to the immune signaling and the cellular senescence that we with telomeric DSBs induced by in of telomere this we a of in cells to findings B. 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C. Gao A. L. Y. R. T. J. K. T. J. S. K. T. of cGAS interferon in Commun. PubMed Scopus Google Scholar). not micronuclei but as with and cells of immune signaling genes cells the of cells for also cells to and these findings that the cGAS-mediated cytosolic DNA pathway is to cellular senescence in response to dysfunctional telomeres. Cellular senescence cell and in and We can at of cellular replicative senescence, which telomere shortening, and stress-induced premature senescence, which not telomere shortening. Although many premature senescence, this study that the of cytosolic chromatin fragments caused by dysfunctional telomeres initiates the cGAS-mediated cytosolic DNA-sensing pathway and the premature senescence phenotype. 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DNA induce chromosome in human 2011; PubMed Scopus Google Scholar). dysfunctional telomeres with DDR signaling to micronuclei cGAS-mediated immune signaling and a telomere premature senescence phenotype. study that the activation of the of telomere pathway causes an telomere DNA to the that is by the cGAS DNA and the signaling cascade to which in telomere DNA is to ALT DNA Biol. PubMed Scopus Google Scholar). However, we found that of the micronuclei for telomeric DNA and of the telomeric DNA micronuclei cGAS a that dysfunctional telomeres cytosolic chromatin fragments and activate signaling, which in cell and genomic instability J. R. A. J.M. B. A. J. cell instability during replicative PubMed Scopus Google Scholar). 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