The expanding universe of PARP1-mediated molecular and therapeutic mechanisms

• Published in: Molecular cell Vol. 82; no. 12; pp. 2315 - 2334
• Main Authors: Huang, Dan, Kraus, W. Lee
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.06.2022
• Subjects: ADP-Ribosylation; biomolecular condensate; chromatin; Chromatin - genetics; DNA Damage; DNA damage response; DNA Repair; DNA replication; gene regulation; histone; PARP; PARP inhibitor; PARPi; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; poly(ADP-ribose) polymerase; post-translational modification; Protein Processing, Post-Translational; PTM; ribosome biogenesis; RNA - metabolism; RNA biology; therapeutic resistance; therapeutics; DNA replication; therapeutics; RNA biology; DNA damage response; poly(ADP-ribose) polymerase; PARP inhibitor; PTM; PARP; post-translational modification; chromatin; gene regulation; therapeutic resistance; biomolecular condensate; histone; PARPi; ADP-ribosylation; ribosome biogenesis
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.02.021

ADP-ribosylation (ADPRylation) is a post-translational modification of proteins catalyzed by ADP-ribosyl transferase (ART) enzymes, including nuclear PARPs (e.g., PARP1 and PARP2). Historically, studies of ADPRylation and PARPs have focused on DNA damage responses in cancers, but more recent studies elucidate diverse roles in a broader array of biological processes. Here, we summarize the expanding array of molecular mechanisms underlying the biological functions of nuclear PARPs with a focus on PARP1, the founding member of the family. This includes roles in DNA repair, chromatin regulation, gene expression, ribosome biogenesis, and RNA biology. We also present new concepts in PARP1-dependent regulation, including PAR-dependent post-translational modifications, “ADPR spray,” and PAR-mediated biomolecular condensate formation. Moreover, we review advances in the therapeutic mechanisms of PARP inhibitors (PARPi) as well as the progress on the mechanisms of PARPi resistance. Collectively, the recent progress in the field has yielded new insights into the expanding universe of PARP1-mediated molecular and therapeutic mechanisms in a variety of biological processes. Huang and Kraus review the expanding array of molecular mechanisms underlying the biological, pathological, and therapeutic functions of nuclear PARPs and ADP-ribosylation, including roles in DNA repair, chromatin regulation, gene expression, and RNA biology. They also present emerging concepts, including PAR-dependent post-translational modifications, ADP-ribose spray, and PAR-mediated biomolecular condensate formation.