ADP-ribosylation: An emerging regulator of the epigenome.

ADP-ribosylation (ADPRylation) is a post-translational modification best known for its roles in DNA damage responses and cytoplasmic signaling, but it also serves important functions in epigenome regulation. In the nucleus, ADPRylation modulates chromatin structure and gene expression through the coordinated modification of histones and chromatin-associated proteins. Although poly(ADP-ribosyl)ation (PARylation) has dominated the field, particularly as therapeutic targets in DNA repair deficient malignancies, a gap remains in our understanding of how mono(ADP-ribosyl)ation (MARylation)-mediated by mono(ADP-ribosyl) transferases (MARTs)-functions as a discrete, site-specific epigenomic mark. Nuclear MART-mediated ADPRylation modulates the activity, localization, and complex assembly of epigenomic enzymes, and directly modifies histones to influence chromatin accessibility and transcriptional dynamics. These reversible modifications intersect with canonical epigenomic marks, enabling rapid, context-dependent control of gene expression. Emerging studies further implicate dysregulated nuclear ADPRylation in cancer, where altered MARylation of chromatin regulators and transcription factors contributes to aberrant gene expression programs and may represent a novel class of therapeutic vulnerabilities. In this review, we synthesize emerging insights into nuclear ADPRylation, with a focus on MART-mediated regulation of histones and chromatin enzymes, and discuss how this regulatory layer expands current models of epigenomic control in physiology and how its alterations drive oncogenesis, offering novel, nonsynthetically lethal avenues for targeted cancer therapy.