Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes Rebecca Gupte,1,2 Ziying Liu,1,2 and W. Lee Kraus1,2 1Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 2Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA The discovery of poly(ADP-ribose) >50 years ago opened units derived from β-NAD+ to catalyze the ADP-ribosyla- a new field, leading the way for the discovery of the tion reaction. These enzymes include bacterial ADPRTs poly(ADP-ribose) polymerase (PARP) family of enzymes (e.g., cholera toxin and diphtheria toxin) as well as mem- and the ADP-ribosylation reactions that they catalyze. bers of three different protein families in yeast and ani- Although the field was initially focused primarily on the mals: (1) arginine-specific ecto-enzymes (ARTCs), (2) biochemistry and molecular biology of PARP-1 in DNA sirtuins, and (3) PAR polymerases (PARPs) (Hottiger damage detection and repair, the mechanistic and func- et al. 2010). Surprisingly, a recent study showed that the tional understanding of the role of PARPs in different bio- bacterial toxin DarTG can ADP-ribosylate DNA (Jankevi- logical processes has grown considerably of late. This has cius et al. 2016). How this fits into the broader picture of been accompanied by a shift of focus from enzymology to cellular ADP-ribosylation has yet to be determined. a search for substrates as well as the first attempts to In this review, we focus on the mono(ADP-ribosyl)ation determine the functional consequences of site-specific (MARylation) and poly(ADP-ribosyl)ation (PARylation) of ADP-ribosylation on those substrates. Supporting these glutamate, aspartate, and lysine residues by PARP family advances is a host of methodological approaches from members. While many reviews have been written on chemical biology, proteomics, genomics, cell biology, PARPs in the past decade, we highlight the current trends and genetics that have propelled new discoveries in the and ideas in the field, in particular those discoveries that field. New findings on the diverse roles of PARPs in chro- have been published in the past 2–3 years. matin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, vi- PARPs and friends: writers, readers, erasers, and feeders ral infections, and cancer. These studies have begun to re- PARPs interact physically and functionally with a set of veal the promising ways in which PARPs may be targeted accessory proteins that play key roles in determining the therapeutically for the treatment of disease. In this re- overall outcomes in PARP-dependent pathways. By bor- view, we discuss these topics and relate them to the future rowing from and adding to descriptions used by the his- directions of the field. tone modification field (Hottiger 2015), PARPs can be thought of as “writers” of ADP-ribose, and the accessory proteins can be thought of as “readers” (ADP-ribose-bind- ADP-ribosylation is a reversible post-translational modifi- ing domains [ARBDs]), “erasers” (ADP-ribose and PAR cation (PTM) of proteins resulting in the covalent attach- hydrolases), “feeders” (NAD+ synthases), and “consum- ment of a single ADP-ribose unit [i.e., mono(ADP-ribose) ers” (NAD+ hydrolases) (Fig. 1). These are elaborated on (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ri- in more detail below. bose) (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 ADP- The PARP family: ADP-ribose writers ribosyl transferase (ADPRT) enzymes that use ADP-ribose The PARP family consists of 17 members that have distinct structural domains, activities, subcellular [Keywords: poly(ADP-ribose) (PAR); mono(ADP-ribose) (MAR); poly © 2017 Gupte et al. This article is distributed exclusively by Cold Spring (ADP-ribose) polymerase (PARP); gene regulation; DNA repair; RNA Harbor Laboratory Press for the first six months after the full-issue biology] publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding author: [email protected] After six months, it is available under a Creative Commons License Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.291518. (Attribution-NonCommercial 4.0 International), as described at http:// 116. creativecommons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 31:101–126 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/17; www.genesdev.org 101 Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Gupte et al. (except for PARP-3 and PARP-4), the glutamate residue is replaced with isoleucine, leucine, or tyrosine, which is associated with the absence of polymerase activity. Al- though PARP-3 and PARP-4 have the H-Y-E motif, their structurally distinct donor (“D”) loop may explain the lack of polymerase activity by these family members. Strikingly, PARP-9 and PARP-13 do not have the con- served histidine residue in their NAD+-binding pockets, which is likely to account for the lack of catalytic activity (Vyas et al. 2014). What’s in a name? PARPs or ARTDs (ADPRTs, diphtheria toxin-like)? The PARP family of proteins is defined by the presence of Figure 1. A variety of effectors mediate intracellular ADP-ribo- the conserved PARP catalytic domain. Historically, all sylation dynamics. PARPs act as “writers” that add ADP-ribose members of the family were named based on the polymer- moieties to target proteins. The NAD+ required for these PARP- ase activity of the founding member, PARP-1, even mediated ADP-ribosylation reactions is supplied by nicotinamide though many family members have MART activity. Re- mononucleotide adenylyl transferases (NMNATs; “feeders”). cent discussions in the PARP field have centered around The ADP-ribose units on target protein can be recognized by the need to reform the PARP nomenclature. Hottiger “readers” containing macro, WWE, or PAR-binding zinc finger et al. (2010) have proposed using the term ARTD, which (PBZ) domains. The removal of ADP-ribose chains is catalyzed represents the basic catalytic activity of the proteins. While “ ” by erasers, which include PAR glycohydrolase (PARG), ADP- some aspects of the new nomenclature are an improve- ribosyl hydrolase 3 (ARH3), TARG, and MacroD1/D2. NAD+ lev- ment, the vast majority of the published literature has els can be modulated by NAD+ “consumers,” such as PARPs, sir- tuins, NADases, and CD38, which hydrolyze NAD+. used the older PARP nomenclature. In addition, the devel- opment of PARP inhibitors (PARPis) and their frequent dis- cussion in the popular press may make the “PARP” nomenclature difficult to replace. Furthermore, the use of localizations, and functions (Gibson and Kraus 2012; Vyas two different names for each PARP protein may cause con- et al. 2013, 2014). PARPs can be thought of as ADP-ribose fusion. The most important distinction for the field now “writers,” that covalently attach (“write”) ADP-ribose seems to be between the MARTs and the poly(ADP-ribo- units on substrate proteins (Fig. 1). syl) transferases. Recently, the terms “monoPARP” and Based on their structural domains and functions, the “polyPARP” have gained some traction as jargon in the different PARPs can be broadly classified as DNA-depen- field, but we prefer the terms “monoenzyme” and “poly- dent PARPs (PARP-1, PARP-2, and PARP-3), Tankyrases enzyme” due to the obvious oxymoron and redundancy, re- (PARP-5a and PARP-5b), Cys–Cys–Cys–His zinc finger spectively, of the former terms. These terms work equally (CCCH)-containing and WWE PAR-binding domain- well with the PARP and ARTD nomenclature (e.g., PARP containing PARPs (PARP-7, PARP-12, PARP-13.1, and monoenzyme and ARTD polyenzyme). Clearly, the field PARP-13.2), and PAR-binding macrodomain-containing needs to adopt a more sensible, consistent, and universal “macro” PARPs (PARP-9, PARP-14, and PARP-15) (Ame nomenclature. Borrowing from the words of Marshall et al. 2004; Vyas et al. 2013). The PARP family members McLuhan, we must not let the naming of PARPs become can also be categorized according to their catalytic activi- a numbing blow from which the field never recovers. ties: “mono,”“poly,” or inactive. The PARP “monoen- zymes” [i.e., mono(ADP-ribosyl) transferases (MARTs); ARBDs: ADP-ribose readers i.e., PARP-3, PARP-4, PARP-6, PARP-10, PARP-14, PARP-15, and PARP-16] catalyze the addition of a single Studies over the past decade have led to the discovery of ADP-ribose unit on target proteins through a process called motifs, domains, or modules in proteins that can bind to MARylation (Vyas et al. 2014). The PARP “polyenzymes” various forms of ADP-ribose on PARP substrate proteins (i.e., PARP-1, PARP-2, PARP-5a, and PARP-5b) catalyze and function as “readers” (Fig. 1). These ARBDs include the polymerization of ADP-ribose units through α(1 → 2) PAR-binding motifs (PBMs), macrodomains, PAR-binding O-glycosidic bonds in linear or branched chains (Gibson zinc finger (PBZ) modules, and WWE domains (Table 1; and Kraus 2012). In contrast, no enzymatic activity has Kalisch et al. 2012; Barkauskaite et al. 2013; Karlberg been described for PARP-9 and PARP-13 (Vyas et al. 2014). et al. 2013; Krietsch et al. 2013). Other less well character- The catalytic domain of many PARPs contains an ized ARBDs include (1) the phosphopeptide-binding Fork- “H-Y-E” (His–Tyr–Glu) motif.