Abstract
The nuclear acetyltransferase p300 is a chromatin-modifying enzyme that facilitates gene transcription by modifying histone-DNA interactions and promoting the transcriptional activation properties of numerous transcription factors. p300 and its paralogue, CBP (CREB-binding protein) are implicated in a wide range of essential biological processes, however, the extent to which p300 has independent tissue- or signal-specific functions has been a matter of dispute. Here, I used gene targeting, gain-of-function and knockdown models to show that the myocardial response to oxidative stress is obligatorily dependent on the cellular availability of p300, and that this availability is dynamically modulated as part of an acute stress response. p300 was found to promote cytoprotection, reduce oxidative stress, increase cellular pro-survival kinase signaling, and enhance DNA damage repair and therefore preventing the onset of organ dysfunction after oxidative injury. I have not only established that p300-mediated acetylation is required for its induction but also for regulating DNA damage signaling and survival response through its downstream effectors, Acetyl-Histone 3 (Lysine 56) and Acetyl-STAT3, respectively. Mice with heterozygous deletion of p300 show premature aging phenotype with features including graying, osteoporosis, dermal thinning, and sebaceous gland hypertrophy, increased immunoreactivity for p16ink4a, and significantly shortened lifespan without evidence of any systemic disease. My work suggests that p300 is a critical and limiting component of the DNA damage response, and that loss of p300 causes cellular senescence and organismal aging. Additionally, small molecule activators of p300 such as Trichostatin A and SAHA increased the DNA damage response and cardiac myocyte survival in a p300-dependent manner. My work establishes a paradigm for the rational targeting of p300 activity in the divergent settings of acute and chronic cardiovascular diseases.