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p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression

View ORCID ProfileMonisankar Ghosh, Suchandrima Saha, Jinyu Li, David C Montrose, Luis A. Martinez
doi: https://doi.org/10.1101/2022.05.26.493595
Monisankar Ghosh
aDepartment of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11790, USA
bStony Brook Cancer Center, Stony Brook, NY,, 11790, USA
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  • ORCID record for Monisankar Ghosh
Suchandrima Saha
aDepartment of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11790, USA
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Jinyu Li
aDepartment of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11790, USA
bStony Brook Cancer Center, Stony Brook, NY,, 11790, USA
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David C Montrose
aDepartment of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11790, USA
bStony Brook Cancer Center, Stony Brook, NY,, 11790, USA
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Luis A. Martinez
aDepartment of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11790, USA
bStony Brook Cancer Center, Stony Brook, NY,, 11790, USA
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  • For correspondence: luis.martinez@stonybrookmedicine.edu
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Abstract

Tumor suppression by p53 is known to involve cell autonomous and non-cell autonomous mechanisms. p53 has been shown to suppress tumor growth by modulating immune system functions, however, the mechanistic basis for this activity is not well understood. Here we report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 ubiquitin-dependent degradation. The accumulation of cytosolic DNA due to p53’s suppression of TREX1 activates the cytosolic DNA sensor, cGAS and its downstream effectors STING/TBK1/IRF3 resulting in induction of Type I interferons. TREX1 overexpression sufficed to block WTp53 activation of the cGAS/STING pathway. WTp53 mediated induction of type I interferon (IFNB1) response could be suppressed by cGAS/STING knockout. We find that p53’s tumor suppressor activities are compromised by loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell intrinsic and cell extrinsic tumor suppressor activities.

Competing Interest Statement

The authors have declared no competing interest.

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Posted May 26, 2022.
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p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression
Monisankar Ghosh, Suchandrima Saha, Jinyu Li, David C Montrose, Luis A. Martinez
bioRxiv 2022.05.26.493595; doi: https://doi.org/10.1101/2022.05.26.493595
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p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression
Monisankar Ghosh, Suchandrima Saha, Jinyu Li, David C Montrose, Luis A. Martinez
bioRxiv 2022.05.26.493595; doi: https://doi.org/10.1101/2022.05.26.493595

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