PACS-2 regulates SIRT 1-mediated deacetylation of p53 following DNA damage

Following DNA damage, p53 activates transcriptional programs that drive cell‑cycle arrest, apoptosis, and senescence, and these outcomes depend on regulation by cofactors and post‑translational modifications. Because SIRT1 deacetylates and represses p53, mechanisms controlling the SIRT1–p53 axis are critical for effective DNA damage responses. This study identifies the membrane‑trafficking protein PACS‑2 as an inhibitor of SIRT1‑mediated p53 deacetylation. PACS‑2 directly binds SIRT1, promotes p53 acetylation, and supports p21 expression. Loss of PACS‑2 decreases p53 acetylation and increases apoptosis in a SIRT1‑, p53‑, and p21‑dependent manner. These findings establish PACS‑2 as a key regulator of the SIRT1–p53–p21 pathway during DNA damage.