PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

Abstract

The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…PARP is an abundant enzyme present throughout the phylogenetic spectrum. Although it is primarily studied in the nucleus Jagtap and Szabó, 2005;Gibson and Kraus, 2012;Gupte et al, 2017), emerging evidence also demonstrates its localization and multiple roles in mitochondria (see Brunyanszki et al, 2016). PARP plays a variety of important physiological roles in DNA repair, chromatin remodelling, cell differentiation, transcriptional regulation, cell cycle control and programmed cell death (reviewed in Virág and Szabó, 2002;Jagtap and Szabó, 2005;Gibson and Kraus, 2012;Gupte et al, 2017).…”

Insights into the biogenesis, function, and regulation of ADP-ribosylation

“…In addition, PARPs play vital roles in regulating cellular stress responses related to the quality control of DNA, RNA and protein—specifically, the DNA damage response, the cytoplasmic stress response, and the unfolded protein response, respectively 12,19,21,46 . PARPs also play roles in the general, nonstress, nondefense pathways in cells by modulating gene expression, telomere length, transcriptional regulation, translation, mRNA stability, cell signaling, cell division and cell motility 17,20,21,33,34,47–49 . Furthermore, they also play important roles in regulating protein stability by targeting proteins for ubiquitylation by directly PARylating them 13–16 .…”

“…Three high-affinity PAR binding domains have been identified: the tryptophan–tryptophan–-glutamate (WWE) domain, the poly(ADP-ribose)-binding zinc finger (PBZ) domain, and ‘macro’ domains. In addition, a lower affinity PAR-binding domain was identified called the PAR binding motif 49 . Macro domains also bind MAR, and examples have been found in bacterial MAR hydrolases that utilize Macro domains to bind and hydrolyze ADP-ribosylated proteins 26 .…”

“…For example, the duration of the cellular effects of bacterial toxins on their host proteins depends on the sustained modification of the target proteins 29 , and the DNA damage repair signal sent by PARP1 is dependent on a balance of sustained PARP1 activation and the regulation of PARG, the hydrolase that degrades PAR and reverses the ADPr signal 49 . Many factors affect the turnover of ADPR modifications, and most of these are likely dependent on the specific biology of the targets and the pathways affected.…”

Genome integrity and disease prevention in the nervous system

“…Increased PARP activity can deplete cellular NAD levels, leading to neurotoxicity (Gupte et al 2017;Narne et al 2017). This was confirmed in mice with XRCC1 deleted in the brain , in which the characteristic loss of cerebellar interneurons was rescued by coincident deletion of PARP1 (Hoch et al 2017).…”