Pathological and physiological roles of ADP-ribosylation: established functions and new insights
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Karla L.H. Feijs-Žaja
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Nonso J. Ikenga
Abstract
The posttranslational modification of proteins with poly(ADP-ribose) was discovered in the sixties. Since then, we have learned that the enzymes involved, the so-called poly(ADP-ribosyl)polymerases (PARPs), are transferases which use cofactor NAD+ to transfer ADP-ribose to their targets. Few PARPs are able to create poly(ADP-ribose), whereas the majority transfers a single ADP-ribose. In the last decade, hydrolases were discovered which reverse mono(ADP-ribosyl)ation, detection methods were developed and new substrates were defined, including nucleic acids. Despite the continued effort, relatively little is still known about the biological function of most PARPs. In this review, we summarise key functions of ADP-ribosylation and introduce emerging insights.
1 Introduction
The modification of proteins after their translation, known as posttranslational modification, is a key mechanism to increase proteomic diversity. This enables cells to respond dynamically to changes in conditions. A well-studied example is phosphorylation, where kinases are the enzymes which add phosphates to their substrates. Phosphatases reverse the modification and dedicated domains bind to it to initiate further signalling. ADP-ribosylation is a posttranslational modification where ADP-ribose (ADPr) is transferred from β-nicotinamide adenine dinucleotide (NAD+) to substrate proteins under concomitant release of nicotinamide (Figure 1). First described in the sixties, the enzymes executing this reaction were thought to be poly(ADP-ribosyl)polymerases (PARPs) (Chambon et al. 1963). Later work has, however, demonstrated that these enzymes are not polymerases, but instead function as ADP-ribosyltransferases (ARTs). Mammalian cells contain two distinct classes of ARTs, the intracellular ARTDs and the extracellular ARTCs, named for their resemblance to diphtheria or cholera toxins respectively (Hottiger et al. 2010). The amino acids important for catalysis form a triad, which is conserved between the mammalian ARTDs and diphtheria toxin (H-Y-E or derivations thereof in mammalian ARTs), and the ARTCs and cholera toxin (R-S-E) (Hottiger et al. 2010). Several toxins with ART activity have been identified, including not only the mentioned diphtheria toxin from Corynebacterium diphtheriae and cholera toxin from Vibrio cholerae, but also SpvB from Salmonella entericum and pertussis toxin from Bordetella pertussis. How the diverse ADP-ribosylating toxins compare to human ARTs and how they mediate bacterial toxicity has been reviewed before (Grimaldi et al. 2015; Hottiger et al. 2010). The diverse toxins and extracellular ARTCs will not be discussed further in this review, which instead focuses on the mammalian ARTDs. The intracellular ARTDs can be further divided in two distinct categories based on their catalytic activities, namely the poly- and monoARTs (Kleine et al. 2008; Luscher et al. 2022a; Vyas et al. 2014). Poly(ADP-ribosyl)ation (PARylation) is generated by iterative transfer of ADPr and has been relatively well studied, whereas less is known about mono(ADP-ribosyl)ation (MARylation). Progress in the study of MARylation has long been hampered by the lack of reliable detection methods. In the last decade mass spectrometry methods have been developed to map modification sites (Bonfiglio et al. 2017a; Buch-Larsen et al. 2020; Colby et al. 2018; Dasovich and Leung 2023; Hendriks et al. 2019; Larsen et al. 2017, 2018; Martello et al. 2016). Moreover, detection reagents were generated which enable studies of MARylation with routine methods such as western blot and immunofluorescence (Bonfiglio et al. 2020; Gibson et al. 2017; Nowak et al. 2020; Weixler et al. 2023). The emergence of these techniques and materials has allowed initial probing into the function of MARylation, where distinct biological functions for the diverse PARPs are emerging. In this review, we aim to provide a succinct overview of the progress that has been made towards understanding the biological function of PARPs and associated MARylation in humans.
Schematic overview of the ADP-ribosylation reaction. PARP enzymes use NAD+ to transfer ADP-ribose onto either nucleic acid or protein substrates, while releasing nicotinamide. This transfer can be repeated by certain PARPs to create chains of poly (ADP-ribose). This reaction can be reversed by hydrolases. The image was generated with BioRender.
2 Writers and erasers of ADP-ribosylation
2.1 PARPs
The human PARP family contains 17 proteins (Luscher et al. 2022a; Schreiber et al. 2006). Their common denominator is the catalytic ART domain, which is located in the enzymes’ C-terminus with the notable exception of PARP4 (Figure 2). PARP1 and PARP2, as well as TNKS1 and TNKS2, are able to perform iterative transfers of ADP-ribose, thereby forming chains of poly(ADP-ribose) (PAR). The other enzymes in this family are monoARTs with exception of PARP13, for which no catalytic activity has been demonstrated to date. Within the ART domains, the three amino acids H-Y-E or variants thereof form a catalytic triad to bind the NAD+ and catalyse the transfer of ADP-ribose. The polyARTs contain a glutamate in their catalytic triad, which has been replaced with other amino acids in the monoARTs (Kleine et al. 2008). It was therefore suggested that the monoARTs use a substrate-assisted catalysis mechanism, where the substrate’s glutamate is essential for the reaction. As this glutamate becomes modified and is not available for further reactions, this provides a putative explanation for their inability to generate PAR. In PARP13 the catalytic triad exists of Y-Y-V, making PARP13 unable to bind NAD+ and render it inactive (Hottiger et al. 2010; Kleine et al. 2008; Vyas et al.; 2014). Beyond the catalytic domains, there is high variability in domains present between the different PARPs. A recurring domain is for example the WWE-domain, which is a protein-protein interaction domain that has been described to also mediate ADPr binding (Aravind 2001; He et al. 2012). Several domains exist which can mediate an interaction with either poly- or mono(ADP-ribose), as reviewed in detail elsewhere (Verheugd et al. 2016). Although all the protein domains present in the diverse PARPs are interesting on their own, in the context of ADP-ribosylation mediated signalling it is worth highlighting that PARP9, PARP14 and PARP15 encode several macrodomains and are therefore sometimes referred to as “macroPARPs” (Schreiber et al. 2006). Some macrodomains serve as readers of either PAR- or MARylation (Forst et al. 2013; Karras et al. 2005; Timinszky et al. 2009), whereas others can reverse the modification (Feijs et al. 2013a; Jankevicius et al. 2013; Sharifi et al. 2013; Slade et al. 2011; Rosenthal et al. 2013). The macroPARPs thus combine ART-activity with domains which either read or reverse the modification. The macrodomain is characterised by a central beta sheet which is flanked by alpha helices (Rack et al. 2016a). Twelve proteins containing in total 16 macrodomains have been identified in humans to date, the majority of which have been linked to ADP-ribosylation as either reader or eraser of the modification (Feijs et al. 2013a; Karras et al. 2005; Till and Ladurner 2009). The presence of ADP-ribosyltransferase, hydrolase and reader domains within a single protein creates in these enzymes an interesting combination of ADPr writing, reading and erasing functionality. As the hydrolase activities of the PARP embedded macrodomains have been discovered only recently (Dukic et al. 2023; Torretta et al. 2023b), it is not known yet what their physiological function is.
Schematic overview of the human PARP family with TRPT1. The depicted domain architecture is based on previous analyses of the PARP family (Schreiber et al. 2006; Suskiewicz et al. 2023). Abbreviations used: ARC, ankyrin-repeat containing; ART, ADP-ribosyltransferase domain; BRCT, BRCA1 C terminus domain; C4, C4 zinc finger motif; CCHC, Cys-Cys-His-Cys zinc finger motif; GPI, glycosylphosphatidylinositol anchor; HD, helical domain; HE, helical extension; ITIHL, inter-alpha-trypsin heavy chain (ITIH)-like (ITIHL) region; KH, K homology domain; Kpta, kinase, phosphatase, and ATPase domain; MD, macrodomain; MVPID, major vault protein interaction domain; MZAP, middle domain of ZnF antiviral protein; Ptrans, putative transmembrane protein; RRM, RNA-recognition motif; RWD, RING finger-containing, WD-repeat-containing, DEAD (DEXD)-like; SAM, sterile alpha motif; SP, signal peptide; TM, transmembrane motif; Tpt1, tRNA 2′-phosphotransferase 1; UIM, ubiquitin interaction motif; vWA, von Willebrand factor type A domain; WGR, conserved TrpGly-Arg motif domain; VIT, vault protein inter-alpha- trypsin; WWE, three conserved residues Trp-Trp-Glu motif domain; ZF, zinc finger.
Recent work has expanded the range of substrates modified by PARPs. Whereas it was initially thought to be a modification of either glutamates or arginines, the advent of advanced mass spectrometry-based techniques has demonstrated that for example also cysteines, threonines, histidines and serines can serve as ADPr acceptor site. Also PARP10 was described to modify amino acids other than glutamates (Garcia-Saura and Schuler 2021), which if true implies that the suggested substrate-assisted catalysis mechanism has to be reconsidered. For PARP1, long believed to exclusively generate PAR on glutamates, it was shown that its activity is redirected towards MARylation on serine residues when in complex with histone PARylation factor 1 (HPF1) (Bonfiglio et al. 2017b; Gibbs-Seymour et al. 2016). As summarised in detail elsewhere, ADP-ribosylation of different amino acids results in different chemical linkages, such as an O-glycosidic bond for acidic residues, serine and tyrosine, an N-glycosidic bond for modified arginines and an S-glycosidic bond for cysteine modification (Rack et al. 2020). To add to this complexity, recently also nucleic acids were identified as PARP substrate. First it was shown that several PARPs can modify DNA in vitro (Munnur and Ahel 2017; Talhaoui et al. 2016; Weixler et al. 2021), followed by the finding that also RNA can be ADP-ribosylated in vitro (Munir et al. 2018; Munnur et al. 2019). Last year, evidence was presented that ADPr capped RNA exists in human cells, especially pronounced upon nutrient starvation, implying that ADP-ribosylation of nucleic acids is not just an in vitro artefact but a true RNA modification (Weixler et al. 2022). In vitro, the ADPr cap blocks translation of RNA and also protects it from degradation, hinting at a function which differs from other cap structures (Ramanathan et al. 2016; Weixler et al. 2022). ADP-ribose can thus be attached to both DNA and RNA in certain conditions. How it influences modified nucleic acids in their cellular function has been not been detailed yet. Similar to other posttranslational and posttranscriptional modifications, ADP-ribosylation of both protein and RNA substrates is reversed by dedicated erasers.
2.2 Hydrolases
As briefly introduced, several macrodomains are active ADP-ribosylhydrolases. Poly(ADP-ribosyl)glycohydrolase (PARG) was the first macrodomain-containing ADP-ribosylhydrolase that was discovered (Brochu et al. 1994; Rack et al. 2016b; Slade et al. 2011). It is a highly active enzyme which rapidly degrades PAR, but which is also an efficient eraser of ADPr-RNA (Munnur et al. 2019; Weixler et al. 2022). The mechanism through which it degrades PAR chains has been well studied (Barkauskaite et al. 2013; Dunstan et al. 2012; Zaja et al. 2012), whereas it is not clear how it removes ADPr from RNA. It is possible that it employs a different mechanism for both substrates, as it cleaves glycosidic bonds in PAR and an O-glycosidic phosphoester bond in ADPr-RNA. Mutation of residues essential for PAR degradation have no effect on ADPr-RNA hydrolysis (Weixler et al. 2022). MACROD1, MACROD2 and terminal ADP-ribose protein glycohydrolase 1 (TARG1) were initially discovered as protein ADP-ribosylhydrolases, removing ADPr from acidic amino acids (Jankevicius et al. 2013; Rosenthal et al. 2013; Sharifi et al. 2013). Later work demonstrated that they are also able to reverse the RNA modification (Munnur et al. 2019; Weixler et al. 2022). MACROD1 localises to mitochondria, MACROD2 is more diffusely distributed and TARG1 localises to the nucleus where it can shuttle to the nucleoli (Zaja et al. 2020). Despite having similar biochemical activity, based on their diverse localisations they are most likely involved in different cellular processes. The latest addition to the macrodomain hydrolase family are macrodomains from PARP9 and PARP14, which have only recently been described to have ADP-ribosylhydrolase activity in vitro (Dukic et al. 2023; Torretta et al. 2023a). Future work will have to uncover their function in vivo. If the catalytic mechanisms for protein and RNA substrates differ, then using different mutations in future work can elucidate whether their protein or RNA ADP-ribosylhydrolase activities are involved in distinct signalling pathways.
A second class of ADPr erasers is formed by the ADP-ribosylhydrolases (ARH). They are structurally distinct from the macrodomain erasers and display different substrate preferences (Rack et al. 2018). ARH1 is an intriguing enzyme, as it is highly active on ADPr-arginine substrates (Moss et al. 1985, 1992), but the extent to which arginine ADP-ribosylation occurs intracellularly is not clear. The only enzymes described to date to ADP-ribosylate arginines are ARTCs, which are localised at the cell membrane facing the extracellular environment (Glowacki et al. 2002; Koch-Nolte et al. 2006). It is unclear whether ARH1 may have additional substrates, or whether any of the intracellular PARPs may modify arginines under specific conditions. Mass spectrometry has identified relatively high levels arginine ADP-ribosylation (Martello et al. 2016), hinting at either the presence of an as yet unknown arginine-specific ART, or the existence of a non-enzymatic modification mechanism. For ARH2 no catalytic activity has been demonstrated, whereas ARH3 can degrade both PAR chains as well as remove ADPr from serine residues (Abplanalp et al. 2017; Fontana et al. 2017; Oka et al. 2006). In total, 8 proteins or protein domains have been identified to date which can reverse ADP-ribosylation, making both protein as well as RNA ADP-ribosylation fully reversible. The notable exception here is cysteine ADP-ribosylation, for which no eraser has been identified yet.
3 DNA damage repair
The first cellular process where ADP-ribosylation was found to play a role, was in DNA damage repair pathways, as summarised in detail elsewhere (Eisemann and Pascal 2020). In short, PARP1, PARP2 and PARP3 contain several domains which can mediate binding to the DNA (Langelier et al. 2012; Rudolph et al. 2021). Binding of DNA leads to dissociation of an autoinhibitory domain (Figure 2, helical domain “HD”) in PARP1 and PARP2 to allow catalytic activity (Dawicki-McKenna et al. 2015; Eustermann et al. 2015; Obaji et al. 2018). These enzymes will then rapidly automodify as well as ADP-ribosylate histones and surrounding proteins, forming large, branched PAR chains. These PAR chains then serve as scaffold to recruit the DNA repair machinery. Breast cancer type 1 susceptibility protein (BRCA1) is one of the proteins which binds to PAR chains and recruits other proteins required for homologous recombination (HR) (Huen et al. 2010). It is thought that PARP1 and PARP2 have overlapping functions (Hanzlikova et al. 2017), as despite a key role in DNA damage repair, PARP1 loss is not lethal and does not lead to increased genomic instability, likely due to PARP2 compensating at least partially (Menissier de Murcia et al. 2003; Shall and de Murcia 2000). In contrast, PARP3 is involved in DNA damage repair in a different manner, as it transfers a single ADPr to for example Ku70, which normally forms a heterodimer with Ku80 and is required for non-homologous end joining (NHEJ) (Boehler et al. 2011; Grundy et al. 2016; Rulten et al. 2011). Two further monoARTs have been implicated in DNA damage repair, PARP10 and PARP14 (Dhoonmoon and Nicolae 2023). Loss of PARP10 leads to an increase in DNA damage in UV-treated HeLa cells and increases sensitivity to DNA damaging agents (Nicolae et al. 2014). Unique in PARP10 is a proliferating cell nuclear antigen (PCNA) interaction peptide-box (PIP-box) (Figure 2), which mediates its interaction with ubiquitinated PCNA and is essential for its role in DNA damage (Nicolae et al. 2014). It was suggested that the PARP10-PCNA complex recruits translesion synthesis polymerase to stalled replication forks, leading to bypassing of the break and thereby promoting genomic stability. It could furthermore be shown that PARP10 overexpression led to a restart of stalled replication forks through an as yet unknown mechanism (Schleicher et al. 2018). Other studies have documented additional functions for PARP10, such as repression of NF-κB signalling (Verheugd et al. 2013), regulation of mitochondrial metabolism (Marton et al. 2018), regulation of kinase activity (Di Paola et al. 2022; Feijs et al. 2013b; Tian et al. 2020) and stress granule formation (Jayabalan et al. 2023). More work is required to confirm whether PARP10 is truly this multifaceted, or whether certain functions are for example restricted to specific cell types, cell cycle phases or developmental stages. Similarly, also for PARP14 several putative roles in diverse signalling networks have been described, including DNA damage repair. Loss of PARP14 reduces DNA repair efficiency via HR and increases sensitivity to DNA damage. This is possibly caused by ADP-ribosylation of DNA repair protein RAD51 homologue 1 (RAD51), a key protein in HR (Nicolae et al. 2015). Similar to PARP10, this is not the only function attributed to PARP14: it was described to be relevant for transcription (Goenka et al. 2007) as well as in immunity (Eddie et al. 2022) and regulation of the cell cycle (O’Connor et al. 2021), where future work will have to address how these distinct functionalities are regulated. Several PARPs thus contribute to DNA damage repair. As faulty DNA repair can be a driver of tumorigenesis (Heinen et al. 2002), it is perhaps not surprising that ADP-ribosylation is relevant in the context of cancer (Figure 3).
Schematic overview of the functions of ADP-ribosylation in (patho)physiology. Depicted are the roles of ADP-ribosylation in (a) DNA damage repair, (b) response to infection and (c) protein degradation, as well as a brief overview of (d) other functions and cellular localisations of PARPs and hydrolases. This image is not exhaustive but intends to provide a global overview of some of the known roles of ADP-ribosylation. The black box indicates that the antiviral mechanism is not well understood. There are many other proposed PARP functions where gaps in our knowledge exist. Abbreviations used: AHR; aryl hydrocarbon receptor, AR; androgen receptor, β-TrcP; beta-transducin repeat containing protein, DTX3L; Deltex E3 ubiquitin ligase 3L, ERa, estrogen receptor alpha; FRA1, Fos-related antigen 1; HIF1a, hypoxia inducible factor 1 alpha; IFNAR, interferon alpha receptor; RNF146, ring finger protein 146; TARG1, terminal ADP-ribosyl glycohydrolase 1. This image was generated with BioRender.
4 Cancer
A substantial effort has been made to develop PARP inhibitors, which started with the establishment of PARP1 inhibitors (Table 1). As has been reviewed previously in detail, PARP inhibitors were the first drugs that were designed based on a principle known as synthetic lethality (Ashworth 2008; Lord and Ashworth 2017). In tumour cells with BRCA1 mutations, which leads to loss of efficient homology directed DNA repair, the additional inhibition of PARP1 becomes lethal. As a result, PARP1 inhibitors are applied for example in BRCA1-deficient ovarian and breast cancers, with clinical trials ongoing in other cancer types. Tumour cells can develop resistance to PARP inhibitors by restoring HR repair or by stabilising replication forks (D’Andrea 2018; Dias et al. 2021). Therefore, clinical trials are also ongoing with combinations of PARP1 inhibitors and other drugs, including for example genotoxic agents or drugs targeting individual components of the DNA repair machinery (Chan et al. 2021). In contrast to PARylation, a role for monoARTs in tumorigenesis has not been firmly established (Richard et al. 2021), although several studies hint that several monoARTs can influence cell growth as summarised in the following paragraph. In 2021, a PARP7 inhibitor, RBN2397, was described to regulate the interferon (IFN) signalling response to nucleic acids in tumour cells, inhibiting cell growth and activating immune signalling. In a lung xenograft model, the PARP7 inhibitor resulted in complete tumour regression (Gozgit et al. 2021). In diverse lung and breast cancer lines, PARP7 modifies the transcription factor Fos-related antigen 1 (FRA1), which is stabilised by ADP-ribosylation (Manetsch et al. 2023). Inhibition of PARP7 destabilises FRA1 leading to the expression of proapoptotic and anti-inflammatory genes, which culminates in apoptosis. PARP7 was therefore suggested as key protein in FRA1-driven cancer. Earlier work described that PARP7 expression is induced by androgen signalling in prostate cancer cells, and that PARP7 modifies the androgen receptor (AR) (Kamata et al. 2021; Yang et al. 2021). The ADP-ribosylated AR is subsequently recognised by the macrodomains present in PARP9, which leads to recruitment of ubiquitin E3 ligase Deltex E3 Ubiquitin Ligase 3L (DTX3L) and modulation of AR-dependent transcription (Yang et al. 2021). PARP7 inhibitors were tested in prostate cancer, and also here PARP7 inhibition led to growth inhibition (Yang et al. 2023). It was suggested that the anti-tumorigenic effect of the inhibitor was caused by trapping of PARP7 at chromatin. In the prostate cancer cells investigated, no effect of PARP7 inhibition was measured on IFN signalling. Several studies thus conclude that PARP7 inhibition may become a valid antitumour strategy. PARP10 overexpression was shown to promote cell growth in one study (Schleicher et al. 2018), whereas in another PARP10 overexpression led to apoptosis (Herzog et al. 2013). As hinted at above, the cellular functions of PARP10 are possibly very diverse, and its overexpression may lead to different phenotypes in different cell types, leaving it uncertain whether PARP10 is relevant in a cancer-context and whether PARP10 inhibition might become a therapeutic option. A screen for genes which are synthetic lethal with PARP14 identified ataxia telangiectasia and Rad3-related protein (ATR) as top hit. ATR is a kinase essential for sensing of DNA damage, followed by activation of the DNA damage checkpoint and cell cycle arrest (Cimprich and Cortez 2008). ATR inhibition in PARP14 deficient cells led to defective replication and mitotic catastrophe (Dhoonmoon et al. 2020). Application of a recently developed PARP14 inhibitor led to an increased antitumour immune response (Schenkel et al. 2021), indicating that PARP inhibitors can become relevant not only to limit cancer cell growth, but also to regulate the tumour microenvironment and the immune response. For PARP11, an inhibitor termed ITK7 has been developed (Kirby et al. 2018). The relevance of PARP11 was tested in a mouse xenograft model, where chimeric antigen receptor (CAR)-T cells were applied as therapeutic strategy. CAR-T cells derived from PARP11−/− mice had a higher tumoricidal activity due to stabilisation of the interferon-α/β receptor (IFNAR). PARP11 activity was shown to lead to internalisation of IFNAR (Guo et al. 2019b; Zhang et al. 2022).
Not only the writers of ADP-ribosylation may play a role in tumorigenesis, also the erasers may be of relevance. For MACROD1, several articles indicate that its overexpression may drive cell proliferation and migration under certain conditions. However, there is some discrepancy between publications leaving it unclear whether or not it is relevant for tumorigenesis as reviewed in detail elsewhere (Feijs et al. 2020). Inhibition of PARG may exacerbate replication deficiencies in cancer cells and might also become a future cancer drug target (Slade 2020).
Overview of the available PARP and PARG inhibitors.
| Inhibitor name | Target | Effects | References |
|---|---|---|---|
| Several incl. olaparib and veliparib | PARP1/2 | Effective in BRCA1-deficient cancers. Frequent toxicities observed, as well as inhibitor resistance. | Lord and Ashworth (2017), Dias et al. (2021) |
| XAV939 | TNKS1/2 | Inhibits Wnt signalling. | Huang et al. (2009) |
| RBN-2397 | PARP7 | Regulation of interferon response. Reduced growth of several cancer cell types. | Gozgit et al. (2021), Sanderson et al. (2023) |
| KMR-206 | |||
| OUL35 | PARP10 | ? | Venkannagari et al. (2016) |
| ITK7 | PARP11 | Influences PARP11 localisation; regulates interferon receptor alpha levels. | Kirby et al. (2018); Zhang et al. (2022) |
| RBN-012759 | PARP14 | Regulates inflammatory response in tumour explants. | Schenkel et al. (2021) |
| PDD00017273 | PARG | Stabilises PARylation. In vivo effects not known due to low bioavailability. | James et al. (2016) |
5 Protein degradation
Besides its role in DNA damage, PARylation was also described to be important as a mark for protein degradation. TNKS1 and TNKS2 PARylate axin, leading to ubiquitination and subsequent degradation of axin (Huang et al. 2009). This is dependent on the E3 ligase Ring Finger Protein 146 (RNF146, also known as Iduna), which ubiquitinates axin depending on its PARylation (Callow et al. 2011; Zhang et al. 2011). Axin is a key protein in the β-catenin destruction complex, which is essential for the regulation of Wnt signalling. The ubiquitinated axin is degraded, which leads to the release of β-catenin from the destruction complex and results in enhanced Wnt signalling (Ranes et al. 2021). TNKS inhibitors have been proposed as Wnt inhibitors, as inhibition of TNKS leads to stabilization of axin and inhibition of β-catenin (Huang et al. 2009; Mariotti et al. 2017). In this example, substrate proteins are first PARylated by TNKS1/2, which forms a scaffold for specific ubiquitin E3 ligases to bind their substrate mediated by their WWE-domain. This then enables the ligases to poly-ubiquitinate the proteins, leading to their proteasomal degradation. TNKS1 and TNKS2 interact with a distinct class of E3 ligases: the RING ubiquitin-interacting motif (UIM) family which also bind to and ubiquitinate TNKS in an ADPr-dependent manner (Perrard and Smith 2023). Also MARylation may be involved in regulation of protein stability. The expression of PARP7 can be induced by the aryl hydrocarbon receptor (AHR) following exposure to 2,3,7,8-tetrachloordibenzo-p-dioxin (referred to as “dioxin” hereafter) (Ma et al. 2001; MacPherson et al. 2013), oestrogen receptor α (Rasmussen et al. 2021), and hypoxia-inducible factor-1 (HIF-1 α) (Zhang et al. 2020). In a negative feedback loop, PARP7 decreases the protein levels of these receptors through its MARylation activity (MacPherson et al. 2013; Rasmussen et al. 2021; Zhang et al. 2020). In mouse embryonic fibroblasts (MEFs), knockout of the E3 ligase Cullin-4B (Cul4B) led to reduced AHR nuclear export and degradation after dioxin treatment. Additional knockdown of PARP7 in Cul4B knockout MEFS completely abolished AHR translocation and degradation (Rijo et al. 2021). AHR is thus degraded by the proteasome in a PARP7 dependent manner. Catalytically active PARP7 forms nuclear bodies, which recruit both HIF-1α and HECT, UBA and WWE Domain Containing E3 Ubiquitin Protein Ligase 1 (HUWE1) E3 ubiquitin ligase to promote ADPr-dependent HUWE1-mediated ubiquitination and subsequent degradation of HIF-1α (Zhang et al. 2020). In contrast to this, MARylation of the transcription factor FRA1 by PARP7 stabilises FRA1 (Manetsch et al. 2023). There are thus examples where PARylation leads to recruitment of specific ubiquitin E3 ligases and subsequent protein degradation, whereas MARylation has been described as both a factor inducing subsequent protein degradation, as well as a mark which stabilises modified proteins. Whether this is a more common mechanism regulating protein degradation, as lysine 48-linked ubiquitination is, or whether it leads to degradation of few specific substrates remains to be determined. Failures in mechanisms regulating protein turnover have been identified as cause of several neurodegenerative disorders, raising the question whether ADP-ribosylation may be involved in this pathological condition.
6 Neurodegeneration
Common causes of neurodegenerative disorders include but are not limited to protein misfolding, defective degradation and aggregation. The pathological hallmarks of several neurodegenerative disorders are caused by abnormal interactions between proteins resulting in deposition of self-aggregating misfolded proteins with formation of high-ordered insoluble fibrils. Diseases of protein toxicity due to deregulation of protein maintenance include Alzheimer’s, Parkinson’s and Huntington’s disease (Jellinger 2010). A homozygous mutation of the ADP-ribosylhydrolase TARG1 gene leads to a severe neurodegenerative phenotype (Sharifi et al. 2013), with thus far unknown underlying mechanism. More evidence exists of involvement of ARH3 in neurodegenerative disease. Several ARH3 variants were identified as the cause of a progressive neurodegenerative disorder in nine affected individuals from seven families (Danhauser et al. 2018), and similar phenotypes were observed in six further families (Ghosh et al. 2018). Later case reports have termed the neurological disorder caused by defective ARH3 “stress-induced childhood-onset neurodegeneration with variable ataxia and seizures” (CONDSIAS) (Aryan et al. 2020; Bajaj et al. 2022; Lindskov et al. 2024; Mishra et al. 2021; Ozturk et al. 2022). Illness onset in these patients is believed to be triggered by stress, explaining why disease onset can occur at different ages. It could furthermore be shown that mutations in ARH3 not only influence MARylation levels, but also lead to reduced levels of specific chromatin modifications, such as histone 3 lysine 9 acetylation. This deregulates transcription, however, how this causes the observed neurological phenotypes remains to be determined (Hanzlikova et al. 2020). As ARH3 reverses both PARylation as well as MARylation on serine residues (Abplanalp et al. 2017; Oka et al. 2006), which are both generated by PARP1/2, it has been reasoned that inhibition of PARP1/2 might serve as therapeutic strategy for these patients (Lindskov et al. 2024). Not only hydrolases, also mutations in transferases can lead to severe illness, as neurodevelopmental phenotypes have been observed in patients with PARP6 and PARP10 mutations. PARP6 mutations were found in six patients presenting with diverse clinical manifestations including epilepsy, microencephaly and intellectual disabilities. In a mouse model, the PARP6 protein is enriched in neurons where its catalytic activity was shown to be important for postnatal survival (Vermehren-Schmaedick et al. 2021). Loss of PARP6 activity thus appears to be detrimental for neuronal function, although its modus operandi needs to be determined. A patient with a severe developmental disorder was found to have a mutation in PARP10, leading to PARP10 deficiency. Cells from this patient are more sensitive to DNA damaging agents and it was speculated that the loss of PARP10’s function in DNA damage repair caused the neurodevelopmental phenotype (Shahrour et al. 2016). Although the underlying mechanisms are not yet fully understood, from the presented case reports it becomes apparent that maintaining the ADP-ribosylation balance is essential.
6.1 Immunity
Several lines of evidence indicate that diverse PARPs play a role in immunity. Both PARP9 and PARP14 are induced by inflammatory mediator interferon gamma (IFNγ) and regulate macrophage activation (Higashi et al. 2019; Iwata et al. 2016; Santinelli-Pestana et al. 2023). These works described ADP-ribosylation of STAT1 and STAT6 as underlying mechanism, which has been questioned by others (Begitt et al. 2018). PARP9 was furthermore reported to function as sensor of several RNA viruses (Xing et al. 2021). A yeast-two-hybrid screen identified an interaction between PARP9 and DTX3L (Takeyama et al. 2003), which similar to PARP9 is induced by IFNγ (Juszczynski et al. 2006). The PARP9-DTX3L complex is able to modify ubiquitin with ADP-ribose on the carboxyl group of glycine 76, which is essential for ubiquitin conjugation and is therefore expected to interfere with cellular ubiquitination (Yang et al. 2017). Initially, this catalytic activity was attributed to PARP9. This was surprising as PARP9 was considered as inactive due to alterations of the catalytic triad (Kleine et al. 2008; Vyas et al. 2014). Later work indicated that DTX3L alone can function as ADP-ribosyltransferase independent of PARP9 (Ahmed et al. 2020; Chatrin et al. 2020; Vela-Rodriguez and Lehtio 2022) and can also interact with PARP14 (Bachmann et al. 2014). The ADP-ribosylation of ubiquitin can be reversed by multiple hydrolases (Ashok et al. 2022). The PARP9-DTX3L complex was furthermore described to be involved in antiviral immunity in a multifaceted way. The complex can both ubiquitinate a viral protease, leading to its degradation, and also ubiquitinate a host histone, H2BJ, to promote expression of ISGs (Zhang et al. 2015). It is clear that PARP9-DTX3L is important in immunity, although more work is needed to fully characterise the underlying mechanisms. In 2011, PARP10 was identified as IFN inducible gene in a green fluorescent reporter assay system (Mahmoud et al. 2011). This upregulation was verified in subsequent studies, and has been expanded to additional PARPs. In diverse studies, PARP9-PARP15 have been identified and confirmed as IFN stimulated genes (ISGs) (Atasheva et al. 2012; Eckei et al. 2017; Luscher et al. 2022b; Shaw et al. 2017). The fact that these enzymes are upregulated during infection, as mimicked by IFN stimulation of the cells, hints that they may have a role in combating infection. Indeed, overexpression of PARP7, PARP10 as well as PARP12 leads to reduced viral replication in viral replication assays (Atasheva et al. 2012, 2014; Krieg et al. 2023). Further strengthening the evidence that several PARPs are important in an antiviral response, is the fact that the PARP9, PARP14 and PARP15 genes have evolved rapidly and underwent several rounds of gene loss and rebirth (Daugherty et al. 2014). Lastly, several single stranded RNA viruses encode one or several macrodomain-containing proteins, which are able to reverse ADP-ribosylation introduced by host PARPs (Eckei et al. 2017; Egloff et al. 2006; Fehr et al. 2018; Li et al. 2016). In mouse infection models, inactivating mutations of viral macrodomains led to a lower viral load, indicating that host ADP-ribosylation is involved in the antiviral response in vivo and is counteracted by viral macrodomains (Fehr et al. 2015, 2016). The mechanism underlying PARP11’s antiviral function has been studied, where it was found that PARP11 MARylates F-box/WD repeat-containing protein 1A (FBW1A also known as β-TrCP), a ubiquitin E3 ligase which is activated by the MARylation. This leads to its ubiquitination of the interferon receptor IFNAR, with as consequence degradation of the receptor and modulation of the IFN response (Guo et al. 2019a,b). Also for PARP13 strong evidence exists in support of an antiviral function, however, as PARP13 is believed to be catalytically inactive PARP13 will not be further discussed here. Not only in viral infections does ADP-ribosylation appear to play a role. PARP14 has been studied in the context of infection with Salmonella typhimurium, where PARP14 hindered bacterial growth in mouse macrophages (Caprara et al. 2018). MARylation is thus involved in the host response to several viral and bacterial infections. As the induction of PARPs in response to immune stimuli and their influence on viral replication has been observed by several labs using complementary methods, the postulated involvement of ADP-ribosylation in the response to pathogens represents one of best documented functions of MARylation to date. One exciting question which has not been addressed yet, is whether modification of protein or RNA substrates mediates the PARP-induced response to infection, which undoubtedly will be addressed in future studies. Initial explorations into clinical use of this knowledge have been made. One study reported that PARP14 inhibition limits mucus production in a pulmonary response to allergens, whereas another study reported that PARP14 is required to limit allergic inflammation of the skin (Eddie et al. 2022; Krishnamurthy et al. 2017). It is thus thinkable that specific PARP inhibitors may become of use to limit immune responses in specific conditions, although more work is required to define those conditions as well as underlying mechanisms.
6.2 Emerging functions
In addition to the relatively well-established roles of ADP-ribosylation in DNA damage repair, protein turnover and immunity, several reports also link ADP-ribosylation to additional cellular compartments and signalling networks. In a study comparing the localisation of overexpressed, green fluorescent protein (GFP)-tagged PARPs, several PARPs were found in stress granules (SGs), including PARP12 and PARP13 (Vyas et al. 2013). The SG localisation of overexpressed PARP12 has been confirmed in later work; however, endogenous PARP12 localises to the Golgi. Treatment of cells with sodium arsenite or heat shock also induced endogenous PARP12 to re-localise to SGs, confirming its localisation there (Catara et al. 2017). The functional importance of PARP12 for SGs has not been studied yet. Another monoART was recently found to be required for SG initiation, namely PARP10. In a preprint, it was suggested that PARP10 modifies Ras GTPase-activating protein-binding protein 1 (G3BP1), a core component of SGs, to enable SG assembly. Further analysis indicates that G3BP1 is PARylated, hinting at the involvement of a polyART in addition to the monoART PARP10 (Jayabalan et al. 2023). Previously, it had been shown that PAR is important for SG formation (Leung et al. 2011), clearly indicating that ADP-ribose, either mono-, poly-, or both, is essential for SGs. In the Golgi apparatus, PARP12 was reported to MARylate Golgin, a protein involved in exocytosis. Knockdown of PARP12 led to a dysregulation of exocytosis (Grimaldi et al. 2022). These and other emerging functions need to be further studied to determine how exactly ADP-ribose influences SGs, exocytosis and other cellular processes.
7 Conclusions
ADP-ribosylation is an intriguing, versatile modification of both protein and nucleic acid substrates. In this review, we have provided a broad overview of established as well as emerging functions of this modification. The role of PARylation in response to DNA damage as well as regulator of protein degradation has been relatively well studied. For MARylation, accumulating evidence indicates that it plays an important role in antiviral immunity. The rapid progress in the mass spectrometry field has allowed the visualisation of the ADP-ribosylation landscape in different cell types, tissues and (stress) conditions, and has rendered a staggering amount of ADP-ribosylated proteins. For hardly any of these proteins we understand the consequence of modification. It is essential to now study those individual substrates and determine how ADP-ribosylation impacts on their function, to be able to better understand the still elusive role of ADP-ribosylation in (patho)physiology. Such detailed studies are complicated by several factors. First, the relative uncertainty as to which substrate amino acid is relevant for which PARP enzyme in cells needs to be resolved (Feijs and Zaja 2022). ADP-ribosylation of diverse amino acids has different chemical properties and labilities, and generating samples for western blot has to take this into account. Routine boiling in sodium dodecyl sulphate (SDS) sample buffer will lead to loss of signal if ADP-ribose on glutamates is to be studied (Tashiro et al. 2023; Weixler et al. 2023). Next, the continued development of tools is required to ensure further progress in the field. For many other posttranslational modifications antibodies exist that detect modifications depending on linkages or surrounding peptide backbone, and it would be conductive for further progress to develop similar reagents for ADP-ribosylation. Lastly, the potential contribution of hydrolases to the ADP-ribosylation landscape is sometimes ignored. A simple explanation for this is the lack of inhibitors for all ADP-ribosylhydrolases except PARG. They are an important factor to consider also during cell lysis, where again the parallel with other modifications can be drawn: without inhibiting phosphatases, or deubiquitinases, it is hard if not impossible to detect phosphorylation and ubiquitination in cell lysates. To be able to preserve the ADP-ribosylation status of substrates in cells during lysis, it will be essential to be able to block the relevant de-ADP-ribosylating enzymes, for which further inhibitor development is required.
ADP-ribosylation is thus involved in key physiological processes such as DNA damage repair, protein turnover and immunity, or when deregulated in pathophysiological conditions including cancer and neurodegeneration. A better understanding of these functions will stimulate further development of additional PARP and hydrolase inhibitors as well as potential repurposing of existing inhibitors for several pathological conditions, including as therapy for different cancer types, potential antiviral drug or treatment option for neurodegenerative disorders.
Acknowledgements
We would like to thank Bernhard Lüscher for supporting our lab at the Institute of Biochemistry and Molecular Biology of RWTH Aachen University. We are grateful to the German Research Foundation (DFG) (FE1423/3-1) and the START Program (13/20, 116/22 and 15/24) as well as a Habilitation Stipend from the Medical Faculty of RWTH Aachen University for funding of our ongoing work.
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Research ethics: Not applicable.
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Author contributions: KFZ and RZ generated the images; all authors contributed to writing of the review.
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Competing interests: Not applicable.
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Research funding: Not applicable.
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Data availability: Not applicable.
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Articles in the same Issue
- Frontmatter
- Highlight: GBM Young Investigators Part 5
- Highlight: young research groups in Germany – 5th edition
- Protein persulfidation in plants: mechanisms and functions beyond a simple stress response
- Pathological and physiological roles of ADP-ribosylation: established functions and new insights
- Implications of TRPM3 and TRPM8 for sensory neuron sensitisation
- The complex regulation of Slo1 potassium channels from a structural perspective
- The TOM complex from an evolutionary perspective and the functions of TOMM70
- Insights in caveolae protein structure arrangements and their local lipid environment
- Insights into caudate amphibian skin secretions with a focus on the chemistry and bioactivity of derived peptides
- Analysis of cell cycle stage, replicated DNA, and chromatin-associated proteins using high-throughput flow cytometry
- A tailored cytochrome P450 monooxygenase from Gordonia rubripertincta CWB2 for selective aliphatic monooxygenation
Articles in the same Issue
- Frontmatter
- Highlight: GBM Young Investigators Part 5
- Highlight: young research groups in Germany – 5th edition
- Protein persulfidation in plants: mechanisms and functions beyond a simple stress response
- Pathological and physiological roles of ADP-ribosylation: established functions and new insights
- Implications of TRPM3 and TRPM8 for sensory neuron sensitisation
- The complex regulation of Slo1 potassium channels from a structural perspective
- The TOM complex from an evolutionary perspective and the functions of TOMM70
- Insights in caveolae protein structure arrangements and their local lipid environment
- Insights into caudate amphibian skin secretions with a focus on the chemistry and bioactivity of derived peptides
- Analysis of cell cycle stage, replicated DNA, and chromatin-associated proteins using high-throughput flow cytometry
- A tailored cytochrome P450 monooxygenase from Gordonia rubripertincta CWB2 for selective aliphatic monooxygenation
