PMID- 32540968
OWN - NLM
STAT- MEDLINE
DCOM- 20210219
LR  - 20210808
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 295
IP  - 32
DP  - 2020 Aug 7
TI  - Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP 
      synthase.
PG  - 11144-11160
LID - 10.1074/jbc.RA120.012962 [doi]
AB  - 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.
CI  - (c) 2020 Abdisalaam et al.
FAU - Abdisalaam, Salim
AU  - Abdisalaam S
AD  - Department of Radiation Oncology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, USA.
FAU - Bhattacharya, Souparno
AU  - Bhattacharya S
AUID- ORCID: 0000-0002-8681-6363
AD  - Department of Radiation Oncology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, USA.
FAU - Mukherjee, Shibani
AU  - Mukherjee S
AD  - Department of Radiation Oncology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, USA.
FAU - Sinha, Debapriya
AU  - Sinha D
AD  - Department of Radiation Oncology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, USA.
FAU - Srinivasan, Kalayarasan
AU  - Srinivasan K
AD  - Department of Radiation Oncology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, USA.
FAU - Zhu, Mingrui
AU  - Zhu M
AD  - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA.
FAU - Akbay, Esra A
AU  - Akbay EA
AUID- ORCID: 0000-0002-4149-2529
AD  - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, 
      Texas, USA.
FAU - Sadek, Hesham A
AU  - Sadek HA
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Shay, Jerry W
AU  - Shay JW
AUID- ORCID: 0000-0001-5052-0627
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Asaithamby, Aroumougame
AU  - Asaithamby A
AUID- ORCID: 0000-0001-5195-4224
AD  - Department of Radiation Oncology, University of Texas Southwestern Medical 
      Center, Dallas, Texas, USA Asaithamby.Aroumougame@UTSouthwestern.edu.
LA  - eng
GR  - R01 HL115275/HL/NHLBI NIH HHS/United States
GR  - P30 CA142543/CA/NCI NIH HHS/United States
GR  - C06 RR030414/RR/NCRR NIH HHS/United States
GR  - P50 CA070907/CA/NCI NIH HHS/United States
GR  - R01 AG053341/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200615
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Nucleotides, Cyclic)
RN  - 0 (cyclic guanosine monophosphate-adenosine monophosphate)
RN  - EC 6.- (Ligases)
SB  - IM
MH  - Cell Cycle
MH  - Cellular Senescence/*genetics
MH  - DNA Breaks, Double-Stranded
MH  - Humans
MH  - Ligases/*metabolism
MH  - Nucleotides, Cyclic/*metabolism
MH  - Signal Transduction
MH  - *Telomere
PMC - PMC7415994
OTO - NOTNLM
OT  - CRISPR/Cas
OT  - DNA damage
OT  - DNA damage response
OT  - chromatin
OT  - cyclic GMP-AMP synthase (cGAS)
OT  - genome maintenance
OT  - micronuclei
OT  - senescence
OT  - telomere
COIS- Conflict of interest-J. W. S. has an ownership interest (including patents) in 
      and has an unpaid consultant/advisory board relationship with Maia Biotechnology.
EDAT- 2020/06/17 06:00
MHDA- 2021/02/20 06:00
PMCR- 2021/08/07
CRDT- 2020/06/17 06:00
PHST- 2020/02/10 00:00 [received]
PHST- 2020/06/11 00:00 [revised]
PHST- 2020/06/17 06:00 [pubmed]
PHST- 2021/02/20 06:00 [medline]
PHST- 2020/06/17 06:00 [entrez]
PHST- 2021/08/07 00:00 [pmc-release]
AID - S0021-9258(17)49209-X [pii]
AID - RA120.012962 [pii]
AID - 10.1074/jbc.RA120.012962 [doi]
PST - ppublish
SO  - J Biol Chem. 2020 Aug 7;295(32):11144-11160. doi: 10.1074/jbc.RA120.012962. Epub 
      2020 Jun 15.