Mechanisms governing PARP expression, localization, and activity in cells

Abstract

Poly-(ADP)-ribose polymerases (PARPs) are a family of 17 enzymes in humans that have diverse roles in cell physiology including DNA damage repair, transcription, innate immunity, and regulation of signaling pathways. The modular domain architecture of PARPs gives rise to this functional diversity. PARPs catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD⁺) to targets—proteins and poly-nucleic acids. This enigmatic post-translational modification comes in two varieties: the transfer of a single unit of ADP-ribose, known as mono-ADP-ribosylation (MARylation) or the transfer of multiple units of ADP-ribose, known as poly-ADP-ribosylation (PARylation). Emerging data shows that PARPs are regulated at multiple levels to control when and where PARP-mediated M/PARylation occurs in cells. In this review, we will discuss the latest knowledge regarding the regulation of PARPs in cells: from transcription and protein stability to subcellular localization and modulation of catalytic activity.

Graphical Abstract

Keywords:

• Poly(ADP)-ribose polymerase
• nicotinamide adenine dinucleotide (NAD⁺)
• ADP-ribosylation
• MARylation
• PARylation; allosteric activation

Acknowledgments

The authors thank members of the Cohen Lab for many helpful discussions and careful editing. Figures in this work were largely created with BioRender.com. Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.

Disclosure statement

The authors report no conflict of interest.