Loss of p300 Induces a Rapid Aging Phenotype and Blunts ATM‐initiated DNA Damage Response

Background Aging and genotoxic stress are associated with similar reductions in histone acetylation and p300 HAT activity. Hypothesis Acetyltransferase p300 loss is causally related to DNA damage during aging and genotoxic stress. Methods Physiologic parameters and survival were determined in p300 −/+ mice. p300 was knocked down in neonatal cardiac myocytes using siRNA and compared to a non‐targeting sequence. Doxorubicin (Dox) 1μm was used to model genotoxic stress. Cycloheximide (CY) (5μg/ml) was used to assess p300 stability. Results p300+/− mice exhibited an accelerated aging phenotype with premature graying, reduced bone density, dermal thinning, beta galactosidase activity and p16 ink immunoreactivity, and shortened lifespan (≤ 1 y) without evidence of systemic disease. In cardiac myocytes, DOX caused rapid, sustained p300 stabilization (3.7±1.9 fold vs. control at 8h; p<0.05). p300 knockdown increased DOX‐induced myocyte death (26.9±13.5%; p<0.05) and caspase‐3 cleavage, blunted phosphorylation of H2AX, ATM, and BRCA1, and reduced phosphorylation and acetylation of p53. Converse effects were seen with activation of p300 by HDAC inhibitors TSA and SAHA. Conclusion Genotoxic stress causes a post‐transcriptional stabilization of p300 that is required for the DNA damage response, preventing cell death and apoptosis. Loss of p300 could thereby promote an accelerated aging phenotype.