LAUSR

Simple Summary PARP-1 and poly(ADP-ribosyl)ation control gene expression, DNA repair pathways, and genomic stability in multiple ways, such as affecting chromatin remodelling. This review article summarises how PARP-1 activity directly modifies histone proteins and the enzymes involved in DNA/histone epigenetic modifications to mould chromatin structure during transcription and DNA damage response. Understanding the role of poly(ADP-ribosyl)ation in the epigenetic regulation of chromatin organisation will help clarify resistance mechanisms to PARP inhibitors and highlight the clinical relevance of a combinatory approach based on epigenetic drugs. Abstract The regulation of chromatin state and histone protein eviction have been proven essential during transcription and DNA repair. Poly(ADP-ribose) (PAR) polymerase 1 (PARP-1) and poly(ADP-ribosyl)ation (PARylation) are crucial mediators of these processes by affecting DNA/histone epigenetic events. DNA methylation/hydroxymethylation patterns and histone modifications are established by mutual coordination between all epigenetic modifiers. This review will focus on histones and DNA/histone epigenetic machinery that are direct targets of PARP-1 activity by covalent and non-covalent PARylation. The effects of these modifications on the activity/recruitment of epigenetic enzymes at DNA damage sites or gene regulatory regions will be outlined. Furthermore, based on the achievements made to the present, we will discuss the potential application of epigenetic-based therapy as a novel strategy for boosting the success of PARP inhibitors, improving cell sensitivity or overcoming drug resistance.