ADP-ribosyltransferases, an update on function and nomenclature

Abstract

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD⁺ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.

Keywords: ADP-ribosylation; MARylation; PARP; PARylation; posttranslational modification.

Fig. 1.

ADP-ribosylation is a reversible modification of proteins, nucleic acids, and metabolites. (A) Indicated are ADP-ribosyltransferases (ARTs), which catalyze mono- and poly-ADP-ribosylation (MARylation and PARylation, respectively). Poly-ARTs may modify naïive substrates generating PAR chains. Alternatively, poly-ARTs may use MARylated substrates and extend the modification to form polymers. The modification is removed by ADP-ribosylhydrolases. Some hydrolases degrade PAR chains (e.g., PARG and ARH3), and others cleave the glycosidic bond between the substrate and the proximal ADPr (e.g., MacroD1, MacroD2, TARG1, ARH1 and ARH3). Substrates include proteins, nucleic acids, and metabolites (the latter exemplified by O-acetyl-ADPr). The specificity of the enzymes is not indicated, some are highly selective, while others have broad specificity, including the modification of different classes of substrates. (B) Indicated are proteins with different ADPr acceptor amino acids and the corresponding N-, O-, or S-glycosidic linkages at the 1″ position of the nicotinamide ribose. Additional amino acids that have been detected to be modified include Asp, Asn, Lys, Thr, Tyr, His, Phospho-Ser, and diphthamide. Please note that for Ser-ADPr and Arg-ADPr, and probably for other linkages, the initial products are in the a configuration. Isomerization may occur, which is indicated. Additionally, migration to the 2″- and 3″-OH may happen for Glu-ADPr and Asp-ADPr. (C) Summary of the proposed nomenclature. ARTs represent the superfamily, which consists of 23 families, two being ARTD and ARTC [17,18]. Names that are commonly used for ARTD family members are PARP (the historic abbreviation for poly(ADP-ribose)polymerase) and TNKS (for tankyrase). Here, we propose PARP as a name on its own right, rather than an abbreviation.

Fig. 2.

Domain architecture of ARTD and ARTC family members. Important domains of ARTDs and ARTCs family members are indicated. PARylating members as well as members that have been suggested to be catalytically inactive are highlighted in orange and gray, respectively. All other proteins possess MARylating activity. As discussed in the text, whether PARP9 is active has not been fully clarified. The potential coding region of human ARTC2 carries premature stop codons, displayed are the two proteins expressed from two closely related murine genes. ART, ADP-ribosyltransferase domain; BRCT, BRCA1 C terminus domain; GPI, glycosylphosphatidylinositol anchor; HD, helical domain; MD, macrodomain; MVP^ID, major vault protein interaction domain; RRM, RNA-recognition motif; SAM, sterile alpha motif; SP, signal peptide; TM, transmembrane motif; UIM, ubiquitininteraction motif; vWA, von Willebrand factor type A domain; WGR, conserved Trp-Gly-Arg motif domain; WWE, three conserved residues Trp-Trp-Glu motif domain; ZF, Zinc finger (light green, CCHC-type ZnF1 and ZnF2, CCCC-type ZnF3; purple, CCCH-type ZnF).

Fig. 3.

Summary of the functions of mammalian ART family members. The proteins belonging to the H-Y-[EDQ] clade (in lighter colors) and of the R-[ST]-E clade (in darker colors) are grouped together according to cellular processes in which they are proposed to be involved. The family members that are capable of synthesizing PAR chains are indicated in orange, those that MARylate substrates are in green, proteins for which so far no catalytic activity has been identified are in gray. While PARP and TNKS proteins are intracellular, ARTC proteins are translocated into the endoplasmic reticulum and transported to the plasma membrane. Intracellular and/or organelle associated functions are being discussed. ARTC1–4 are membrane associated through a GPI (glycosylphosphatidylinositol) anchor and ARTC5 is secreted. ARTC2 is not expressed in humans, but in other species. The figure gives an overview on important biological functions that appear to be regulated by ADP-ribosylation, it is not meant to be exhaustive. For details readers are referred to the cited, recent reviews. Please note that ARTC2 is not expressed in humans.