RT Journal Article SR Electronic T1 p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.05.26.493595 DO 10.1101/2022.05.26.493595 A1 Monisankar Ghosh A1 Suchandrima Saha A1 Jinyu Li A1 David C Montrose A1 Luis A. Martinez YR 2022 UL http://biorxiv.org/content/early/2022/05/26/2022.05.26.493595.abstract AB 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 StatementThe authors have declared no competing interest.