Temporal regulation of acetylation status determines PARP1 role in DNA damage response and metabolic homeostasis

Poly(ADP-ribose) polymerase 1 (PARP1) is an abundant nuclear protein involved in DNA repair, chromatin structure, and transcription. However, the regulation of its different functions remains poorly understood. Here, we report the role of PARP1 acetylation status in modulating its DNA repair and transactivation functions. We demonstrate that histone deacetylase 5 (HDAC5) determines PARP1 acetylation at Lys498 and Lys521 sites. HDAC5-mediated deacetylation at Lys498 site regulates PARP1 DNA damage response and facilitates efficient recruitment of DNA repair factors at damaged sites, thereby promoting cell survival. Additionally, HDAC5-mediated deacetylation at Lys521 site promotes PARP1 coactivator function, resulting in induction of proliferative and metabolic genes in an activating transcription factor 4-dependent manner. Thus, PARP1 induces metabolic adaptation to spur malignant phenotype. Our studies in mouse tumor models suggest that pharmacological inhibition of PARP1 enzymatic activity does not block tumor progression robustly as transactivation function remains unperturbed. These findings provide key mechanistic insights into PARP1 regulation and expand its role in tumor development.