Are PARPs promiscuous?

Post-translational modifications exist in different varieties to regulate diverse characteristics of their substrates, ultimately leading to maintenance of cell health. The enzymes of the intracellular poly(ADP-ribose) polymerase (PARP) family can transfer either a single ADP-ribose to targets, in a reaction called mono(ADP-ribosyl)ation or MARylation, or multiple to form chains of poly(ADP-ribose) or PAR. Traditionally thought to be attached to arginine or glutamate, recent data have added serine, tyrosine, histidine and others to the list of potential ADP-ribose acceptor amino acids. PARylation by PARP1 has been relatively well studied, whereas less is known about the other family members such as PARP7 and PARP10. ADP-ribosylation on arginine and serine is reversed by ARH1 and ARH3 respectively, whereas macrodomain-containing MACROD1, MACROD2 and TARG1 reverse modification of acidic residues. For the other amino acids, no hydrolases have been identified to date. For many PARPs, it is not clear yet what their endogenous targets are. Better understanding of their biochemical reactions is required to be able to determine their biological functions in future studies. In this review, we discuss the current knowledge of PARP specificity in vitro and in cells, as well as provide an outlook for future research.