Mono-ADP-ribosylating PARP enzymes in cellular signaling and disease

ADP-ribosyl-transferases (ARTs) are versatile post-translational regulators. Mammalian ARTs include poly-and mono-ADP-ribosylating enzymes, which transfer ADP-ribose molecules deriving from β-NAD+ to their targets. Mono-ADP-ribosylation (MARylation), which is catalyzed by mono-ARTs such as PARP3, PARP6–PARP12 and PARP14–PARP16, tunes the activity of targets involved in fundamental cell processes and various signaling pathways, ranging from those regulating cell survival and proliferation to those modulating the cellular response to stress and viral infection. Recent advancements of techniques that enable the discovery of MARylation targets across cellular compartments have further expanded our knowledge about the physiological roles of these targets and the potential connection between MARylation and the onset of pathologies. Furthermore, increasing efforts in the development of specific drugs targeting the different MARylating PARP proteins are opening avenues for innovative pharmacological treatments. In this Review, we illustrate the cell cycle progression, intracellular membrane trafficking and cellular stress pathways regulated by mono-ART PARP proteins. We then describe what is known about the roles of MARylating PARP proteins in the context of viral infection and cancer. Finally, we discuss potential future directions towards mapping out the complex network of PARP targets and functions.