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The chemical modification of cellular macromolecules by the transfer of ADP-ribose unit(s), known as ADP-ribosylation, is an ancient homeostatic and stress response control system. Highly conserved across the evolution, ADP-ribosyltransferases and ADP-ribosylhydrolases control ADP-ribosylation signalling and cellular responses. In addition to proteins, both prokaryotic and eukaryotic transferases can covalently link ADP-ribosylation to different conformations of nucleic acids, thus highlighting the evolutionary conservation of archaic stress response mechanisms. Here, we report several structural and functional aspects of DNA ADP-ribosylation modification controlled by the prototype DarT and DarG pair, which show ADP-ribosyltransferase and hydrolase activity, respectively. DarT/DarG is a toxin–antitoxin system conserved in many bacterial pathogens, for example in Mycobacterium tuberculosis, which regulates two clinically important processes for human health, namely, growth control and the anti-phage response. The chemical modulation of the DarT/DarG system by selective inhibitors may thus represent an exciting strategy to tackle resistance to current antimicrobial therapies. [ABSTRACT FROM AUTHOR]

PARP1 and PARP2 govern the DNA-damage response by catalysing the reversible post-translational modification ADP-ribosylation. During the repair of DNA lesions, PARP1 and PARP2 combine with an accessory factor HPF1, which is required for the modification of target proteins on serine residues. Although the physiological role of individual ADP-ribosylation sites is still unclear, serine ADP-ribosylation at damage sites leads to the recruitment of chromatin remodellers and repair factors to ensure efficient DNA repair. ADP-ribosylation signalling is tightly controlled by the coordinated activities of (ADP-ribosyl)glycohydrolases PARG and ARH3 that, by reversing the modification, guarantee proper kinetics of DNA repair and cell cycle re-entry. The recent advances in the structural and mechanistic understanding of ADP-ribosylation provide new insights into human physiopathology and cancer therapy. [ABSTRACT FROM AUTHOR]

Despite decades of research on ADP‐ribosyltransferases (ARTs) from the poly(ADP‐ribose) polymerase (PARP) family, one key aspect of these enzymes – their substrate specificity – has remained unclear. Here, we briefly discuss the history of this area and, more extensively, the recent breakthroughs, including the identification of protein serine residues as a major substrate of PARP1 and PARP2 in human cells and of cysteine and tyrosine as potential targets of specific PARPs. On the molecular level, the modification of serine residues requires a composite active site formed by PARP1 or PARP2 together with a specificity‐determining factor, HPF1; this represents a new paradigm not only for PARPs but generally for post‐translational modification (PTM) catalysis. Additionally, we discuss the identification of DNA as a substrate of PARP1, PARP2 and PARP3, and some bacterial ARTs and the discovery of noncanonical RNA capping by several PARP family members. Together, these recent findings shed new light on PARP‐mediated catalysis and caution to 'expect the unexpected' when it comes to further potential substrates. [ABSTRACT FROM AUTHOR]

This study analyzes microplastic ingestion by three deep-water elasmobranch species (Galeus melastomus , Scyliorhinus canicula and Etmopterus spinax) from the Tyrrhenian Sea, discriminating between stomach and intestine contents. The absence of significant differences in frequency and abundance of plastic items into stomachs seems to suggest that ecological diversity among the three sharks does not strongly influence the probability of plastic ingestion in the study area. On the other hand, the detected differences in the microplastic content into the intestine might be due to a different retention time of microplastics, suggesting how feeding habits could influence metabolic features, and therefore affect the recovery of ingested plastic items. This information would improve the future development of marine micro-litter monitoring systems, following the MSFD requirements. Moreover, this study shows that all the three examined elasmobranch species can give important information even with relatively small sample sizes (N ≈ 30), and they could be used as target species for monitoring micro-litter ingestion in deep-water habitats. Image 1 • New proposal for study microplastic presence into stomach and intestine separately. • Deep-water sharks are exposed to microplastic ingestion. • First evidence of plastic ingestion by S. canicula in the Mediterranean Sea. • Retention time affect the recovery of ingested microplastics. • Elasmobranchs could be used for monitoring micro-litter ingestion. Feeding habits could influence the retention time of ingested microplastics, and therefore affect their recovery. [ABSTRACT FROM AUTHOR]

Microplastics debris (<5 mm) are increasingly abundant in the marine environment, therefore, potentially becoming a growing threat for different marine organisms. Through aquatic animals, these can enter in the human food chain, and can be perceived as a risk for consumers' health. Different studies report the presence of particles in marketable shellfish including the world wide commercially grown Pacific oyster Magallana gigas (Thunberg, 1793). The aim of this study is to examine the potential risk of microplastics entering in the human food chain through this shellfish species, investigating the dynamics of the uptake, egestion (faeces) and rejection (pseudofaeces) of microplastics in Pacific oysters under controlled conditions. M. gigas collected from a farm in the San Teodoro lagoon (Italy), were exposed to 60 fluorescent orange polystyrene particles L−1 of known sizes (100, 250 and 500 μm). The uptake of each particle size was 19.4 ± 1.1%, 19.4 ± 2% and 12.9 ± 2% respectively. After exposure M. gigas were left to depurate for 72 h, during which 84.6 ± 2% of the particles taken up were released whilst 15.4 ± 2% were retained inside the shell cavity. No microplastic particles were found in the animals' soft tissues. The results of this study, suggest that depuration is an effective method to reduce presence of large microplastic particles, in the size range 100–500 μm, in M. gigas. Importantly, the data suggests that the burden that could theoretically be up taken by consumers from these shellfish is negligible when compared to other routes. Image 107300 • Pacific oysters are farmed world-wide for human consumption. • M. gigas could be a carrier of microplastic, through adhesion to the shell cavity. • Depuration is an effective method to reduce microplastic in oysters. Microplastic of tested sizes were not retained in the tissues but can be retained in the shell cavity; Depuration is an effective method to reduce microplastics in farmed Pacific oysters. [ABSTRACT FROM AUTHOR]

Abstract The presence of marine litter is a complex, yet persistent, threat to the health and biodiversity of the marine environment, and plastic is the most abundant, and ubiquitous type of marine litter. To monitor the level of plastic waste in an area, and the prospect of it entering the food chain, bioindicator species are used extensively throughout Northern European Seas, however due to their distribution ranges many are not applicable to the Mediterranean Sea. Guidance published for the Marine Strategy Framework Directive suggests that the contents of fish stomachs may be analyzed to determine trends of marine plastic ingestion. In order to equate transnational trends in marine plastic ingestion, the use of standardized fish species that widely occur throughout the basin is favoured, however for the Mediterranean Sea, specific species are not listed. Here we propose a methodology to assess how effective Mediterranean fish species, that are known to have ingested marine plastic, are as bioindicators. A new Bioindicator Index (BI) was established by incorporating several parameters considered important for bioindicators. These parameters included species distribution throughout the Mediterranean basin, several life history traits, the commercial value of each species, and the occurrence of marine litter in their gut contents. By collecting existing data for Mediterranean fish, ranked scores were assigned to each trait and an average value (BI value) was calculated for each species. Based on their habitat preferences, Engraulis encrasicolus (pelagic), Boops boops (benthopelagic), three species of Myctophidae (Hygophum benoiti , Myctophum punctatum and Electrona risso) (mesopelagic), Mullus barbatus barbartus (demersal) and Chelidonichthys lucerna (benthic), were identified as currently, the most suitable fish for monitoring the ingestion of marine plastics throughout the Mediterranean basin. The use of standardized indicator species will ensure coherence in the reporting of marine litter ingestion trends throughout the Mediterranean Sea. Graphical abstract Image 1 Highlights • An index describes suitable marine plastic fish bioindicators in the Mediterranean. • European anchovy is well suited to monitor plastic trends in pelagic environments. • Boops boops appears the most adept plastic bioindicator for benthopelagic habitats. • For marine demersal habitats, Mullus barbatus barbatus is a suitable bioindicator. • The work contributes to standardization of Mediterranean monitoring protocols. Using a novel index, seven species of fish were identified as the most suitable to monitor marine plastic ingestion trends in the Mediterranean Sea. [ABSTRACT FROM AUTHOR]

The poly(ADP-ribose) polymerase (PARP) superfamily of enzymes catalyses the ADP-ribosylation (ADPr) of target proteins by using nicotinamide adenine dinucleotide (NAD+) as a donor. ADPr reactions occur either in the form of attachment of a single ADP-ribose nucleotide unit on target proteins or in the form of ADP-ribose chains, with the latter called poly(ADP-ribosyl)ation. PARPs regulate many cellular processes, including the maintenance of genome stability and signal transduction. In this review, we focus on the PARP family members that possess the ability to modify proteins by poly(ADPribosyl) ation, namely PARP1, PARP2, Tankyrase-1, and Tankyrase-2. Here, we detail the cellular functions of PARP1 and PARP2 in the regulation of DNA damage response and describe the function of Tankyrases in Wnt-mediated signal transduction. Furthermore, we discuss how the understanding of these pathways has provided some major breakthroughs in the treatment of human cancer. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that synthesise ADPribosylation (ADPr), a reversible modification of proteins that regulates many different cellular processes. Several mammalian PARPs are known to regulate the DNA damage response, but it is not clear which amino acids in proteins are the primary ADPr targets. Previously, we reported that ARH3 reverses the newly discovered type of ADPr (ADPr on serine residues; Ser-ADPr) and developed tools to analyse this modification (Fontana et al., 2017). Here, we show that Ser-ADPr represents the major fraction of ADPr synthesised after DNA damage in mammalian cells and that globally Ser-ADPr is dependent on HPF1, PARP1 and ARH3. In the absence of HPF1, glutamate/aspartate becomes the main target residues for ADPr. Furthermore, we describe a method for sitespecific validation of serine ADP-ribosylated substrates in cells. Our study establishes serine as the primary form of ADPr in DNA damage signalling. [ABSTRACT FROM AUTHOR]

MacroD1 is a macrodomain containing protein that has mono-ADP-ribose hydrolase enzymatic activity toward several ADP-ribose adducts. Dysregulation of MacroD1 expression has been shown to be associated with the pathogenesis of several forms of cancer. To date, the physiological functions and sub-cellular localization of MacroD1 are unclear. Previous studies have described nuclear and cytosolic functions of MacroD1. However, in this study we show that endogenous MacroD1 protein is highly enriched within mitochondria. We also show that MacroD1 is highly expressed in human and mouse skeletal muscle. Furthermore, we show that MacroD1 can efficiently remove ADP-ribose from 50 and 30-phosphorylated double stranded DNA adducts in vitro. Overall, we have shown that MacroD1 is a mitochondrial protein with promiscuous enzymatic activity that can target the ester bonds of ADP-ribosylated phosphorylated double-stranded DNA ends. These findings have exciting implications for MacroD1 and ADP-ribosylation within the regulation of mitochondrial function and DNA-damage in vivo. [ABSTRACT FROM AUTHOR]

ADP-ribosylation is a conserved post-translational protein modification that plays a role in all major cellular processes, particularly DNA repair, transcription, translation, stress response and cell death. Hence, dysregulation of ADP-ribosylation is linked to the physiopathology of several human diseases including cancers, diabetes and neurodegenerative disorders. Protein ADP-ribosylation can be reversed by the macrodomain-containing proteins PARG, TARG1, MacroD1 and MacroD2, which hydrolyse the ester bond known to link proteins to ADP-ribose as well as consecutive ADP-ribose subunits; targeting this bond can thus result in the complete removal of the protein modification or the conversion of poly( ADP-ribose) to mono( ADP-ribose). Recently, proteins containing the NUDIX domain - namely human NUDT16 and bacterial RppH - have been shown to process in vitro protein ADP-ribosylation through an alternative mechanism, converting it into protein-conjugated ribose-5′-phosphate (R5P, also known as pR). Though this protein modification was recently identified in mammalian tissues, its physiological relevance and the mechanism of generating protein phosphoribosylation are currently unknown. Here, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1) as the first known mammalian enzyme lacking a NUDIX domain to generate pR from ADP-ribose on modified proteins in vitro. Thus, our data show that at least two enzyme families - Nudix and ENPP/ NPP - are able to metabolize protein-conjugated ADP-ribose to pR in vitro, suggesting that pR exists and may be conserved from bacteria to mammals. We also demonstrate the utility of ENPP1 for converting protein-conjugated mono( ADP-ribose) and poly( ADP-ribose) into mass spectrometry-friendly pR tags, thus facilitating the identification of ADP-ribosylation sites. [ABSTRACT FROM AUTHOR]

ADP-ribosylation is a post-translational modification (PTM) of proteins found in organisms from all kingdoms of life which regulates many important biological functions including DNA repair, chromatin structure, unfolded protein response and apoptosis. Several cellular enzymes, such as macrodomain containing proteins PARG [poly(ADP-ribose) glycohydrolase] and TARG1 [terminal ADP-ribose (ADPr) protein glycohydrolase], reverse protein ADP-ribosylation. In the present study, we show that human Nudix (nucleoside diphosphate-linked moiety X)-type motif 16 (hNUDT16) represents a new enzyme class that can process protein ADPribosylation in vitro, converting it into ribose-5-phosphate (R5P) tags covalently attached to the modified proteins. Furthermore, our data show that hNUDT16 enzymatic activity can be used to trim ADP-ribosylation on proteins in order to facilitate analysis of ADP-ribosylation sites on proteins by MS. [ABSTRACT FROM AUTHOR]

Ambient Assisted Living (AAL) is trying to respond to the ageing process of the population, aiming at the extension of the time in which older people can live in their home environment and giving support to them and to their families. This paper highlights the importance of Artificial Intelligence to provide intelligent and adaptive solutions to assist an elderly patient with his daily activities, while his health conditions are monitored, in order to ensure his security. Thus a Multi-Agent architecture, based on Belief-Desire-Intention (BDI) paradigm, is proposed, modelling an AAL system. The adoption of BDI paradigm tries to represent the behaviours and the tasks of a human caregiver. The paper presents a software implementation of the proposed architecture: the Virtual Carer. By means of a simulation scenario, the main features and capabilities of the system are shown. [ABSTRACT FROM AUTHOR]

The assessment of the distribution and composition of microlitter in the sea is a great challenge. Biological indicators can be an irreplaceable tool since they measure microlitter levels in their environments in a way that is virtually impossible to replicate by direct physical measurements. Furthermore, trends can provide policymakers with statistically robust analysis. We looked into the capacity of multiple fish species to describe the distribution and composition of microlitter vertically across different compartments of the water column. A total of 502 individuals from six selected species (Scomber scombrus, Oblada melanura, Spicara smaris, Boops boops, Merluccius merluccius and Mullus barbatus) were collected on the western side of Sardinia island and allocated to three compartments: surface, mid-water and bottom. The species of the surface exhibited a higher frequency of occurrence (41.89%) of microlitter ingestion, compared to those of the mid-water and bottom (19.60%; 22.58%). A significant difference in the average number of ingested microlitter was found between the surface and the bottom compartment. All the microlitter fragments found were analysed through Fourier Transform Infrared Spectroscopy (FTIR). The comparison of the expected buoyancies of the polymers identified puth faith in the allocation of the species to the respective compartments. Therefore, considering the Marine Strategy Framework Directive objective, this approach could be useful in assessing microlitter distribution and composition vertically across the water column. Image 1 • Fish species and compartments can describe microlitters distribution and composition. • Fish in the surface compartment had the highest incidence of microlitter ingestion. • Average number of microlitter items was significantly different for compartments. • Polymer analysis gave confidence to the allocation of fish species to compartments. This study suggests that by using multiple fish species, allocated to compartments of the water column, we are able to assess vertical microlitter composition and distribution in marine environments. [ABSTRACT FROM AUTHOR]

Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging. [ABSTRACT FROM AUTHOR]

Recently, many studies focus on the ingestion of microplastics by marine biota. Fish exploit almost every kind of marine environment, occupy many ecological niches and are an important food source for human populations worldwide. For these reasons, they seem to represent very appropriate biological indicators of microplastic ingestion. UNEP/MAP SPA/RAC (2018) identified the bogue, Boops boops (Linnaeus, 1758), as a possible target species for monitoring microplastic ingestion in fish populations. This study provides the first report of microplastic ingestion by B. boops from the Tyrrhenian and the Ligurian Seas (Western Mediterranean Sea). Generalized Linear Mixed Models were used to analyse the relationship among biological parameters and environmental factors. A total of 379 bogues were collected in three Italian regions, subject to different anthropogenic pressures (river input, human population, shipping lanes and distance from the coast). Microplastics were detected in the gastrointestinal tract of most individuals (56%) with a mean of 1.8 (±0.2) microplastics per individual. Our study further confirms that this species is able to highlight differences in the ingestion of microplastics according to local anthropization, resulting Latium region to be the most polluted. Fish with lower physical condition are more likely to ingest microplastics, suggesting a relationship with the level of local environmental contamination. Finally, the ingestion of microplastics might be influenced by behavioural differences between sexes. According to our results, males ingest significantly more microplastics than females (p < 0.05). Our research confirms that an extensive knowledge on the biology of a bioindicator species is a priority for developing a valid monitoring strategy, such as the Marine Strategy Framework Directive for European waters. Image 1 • First report on microplastic ingestion by B. boops from the Italian coasts. • Coastal pressures explain the differences found in microplastic ingestion. • Fish with lower physical condition are more likely to ingest microplastics. • Sexual differences in the ingestion of microplastics by B. boops. Coastal pressures and fish condition factor explain the differences found in microplastic ingestion by Boops boops (Linnaeus, 1758) along the Italian coasts (Western Mediterranean Sea). [ABSTRACT FROM AUTHOR]

Oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas show high morbidity and mortality rates. We aimed to investigate the role of the "Chromatin Assembly Factor-1" (CAF-1) p60 and p150 subunits, involved in DNA repair and replication, in OSCC and OPSCC progression and in response to Poly(ADP-ribose) polymerase (PARP)-inhibitors and exposure to ionizing radiation (IR). We immunostained tissue microarrays (TMAs), including 112 OSCC and 42 OPSCC, with anti-CAF-1/p60 and anti-CAF-1/p150 specific antibodies, correlating their expression with prognosis. Moreover, we assessed the sensitivity to PARP inhibitors and the double-strand breaks repair proficiency by cell viability and HR reporter assays, respectively, in HPV-positive and HPV-negative cell lines upon CAF-1/p60 and CAF-1/p150 depletion. The immunohistochemical analysis revealed a significant prognostic value of both tissue biomarkers combined expression in OSCC but not in OPSCC. In in vitro studies, the p60/150 CAF-1 subunits' depletion impaired the proficiency of Homologous Recombination DNA damage repair, inducing sensitivity to the PARP-inhibitors, able to sensitize both the cell lines to IR. These results indicate that regardless of the prognostic meaning of p60/p150 tissue expression, the pharmacological depletion of CAF-1 complex's function, combined to PARP-inhibitors and/or IR treatment, could represent a valid therapeutic strategy for squamous cell carcinomas of head and neck region. [ABSTRACT FROM AUTHOR]

The abundance and distribution of microplastics (MP) were evaluated in six “clean” sites (Italian minor islands) and in two “polluted” areas (near the mouth of two major Italian rivers). Samples of MP, plankton and persistent organic pollutants (POPs) were collected using a manta trawl (MA) and a plankton net (WP2), both lined with a 333 µm mesh net. MP have been confirmed to be ubiquitous since they were found at each site, showing an average density of 0.3 ± 0.04 items/m3 (values ranged from 0.641 to 0.119). When comparing the clean sites with the polluted ones, a significantly higher value of MP was found near the river mouths. The most common types of MP were synthetic filaments (50.24%), followed by fragments (30.39%), thin plastic films (16.98%) and spheres (2.39%). Infrared spectroscopy analysis highlighted that the most abundant polymers were polyethylene (PE-26%), polypropylene (PP-11%), polyethylene-terephthalate/polyester (PET/PEST-8%) and ethylene-vinyl-acetate (EVA-5%). Polychlorinated biphenyls and organochlorine pesticides were detected in all the samples with a high variability among sites and depths. This study adds to the existing information on the distribution of contaminants across the Mediterranean Sea, and is useful to policy makers who wish to implement effective measures to reduce MP pollution. [ABSTRACT FROM AUTHOR]

Among the post-translational modifications, ADP-ribosylation has been for long time the least integrated in the scheme of the structural protein modifications affecting physiological functions. In spite of the original findings on bacterial-dependent ADP-ribosylation catalysed by toxins such as cholera and pertussis toxin, only with the discovery of the poly-ADP-ribosyl polymerase (PARP) family the field has finally expanded and the role of ADP-ribosylation has been recognised in both physiological and pathological processes, including cancer, infectious and neurodegenerative diseases. This is now a rapidly expanding field of investigation, centred on the role of the different PARPs and their substrates in various diseases, and on the potential of PARP inhibitors as novel pharmacological tools to be employed in relevant pathological context. In this review we analyse the role that members of the PARP family and poly-ADP-ribose (PAR; the product of PARP1 and PARP5a activity) play in the processes following the exposure of cells to different stresses. The cell response that arises following conditions such as heat, osmotic, oxidative stresses or viral infection relies on the formation of stress granules, which are transient cytoplasmic membrane-less structures, that include untranslated mRNA, specific proteins and PAR, this last one serving as the "collector" of all components (that bind to it in a non-covalent manner). The resulting phenotypes are cells in which translation, intracellular transport or pro-apoptotic pathways are reversibly inhibited, for the time the given stress holds. Interestingly, the formation of defective stress granules has been detected in diverse pathological conditions including neurological disorders and cancer. Analysing the molecular details of stress granule formation under these conditions offers a novel view on the pathogenesis of these diseases and, as a consequence, the possibility of identifying novel drug targets for their treatment. [ABSTRACT FROM AUTHOR]

ADP-ribosylation is a post-translational modification that can alter the physical and chemical properties of target proteins and that controls many important cellular processes. Macrodomains are evolutionarily conserved structural domains that bind ADP-ribose derivatives and are found in proteins with diverse cellular functions. Some proteins from the macrodomain family can hydrolyze ADP-ribosylated substrates and therefore reverse this post-translational modification. Bacteria and Streptomyces, in particular, are known to utilize protein ADP-ribosylation, yet very little is known about their enzymes that synthesize and remove this modification. We have determined the crystal structure and characterized, both biochemically and functionally, the macrodomain protein SCO6735 from Streptomyces coelicolor. This protein is a member of an uncharacterized subfamily of macrodomain proteins. Its crystal structure revealed a highly conserved macrodomain fold. We showed that SCO6735 possesses the ability to hydrolyze PARP-dependent protein ADP-ribosylation. Furthermore, we showed that expression of this protein is induced upon DNA damage and that deletion of this protein in S. coelicolor increases antibiotic production. Our results provide the first insights into the molecular basis of its action and impact on Streptomyces metabolism. [ABSTRACT FROM AUTHOR]

ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases. [ABSTRACT FROM AUTHOR]

ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition. [Display omitted] • Chromatin serine-linked MARylation is constantly produced throughout the cell cycle • ADP-ribosylation reactions consist of distinct initiation and elongation steps • PARG and ARH3 suppression is synthetically lethal because of accumulation of PARylation • ARH3 deficiency increases PARPi resistance that can be exploited therapeutically Prokhorova et al. show that accumulation of PARylation, but not MARylation, is highly toxic to the cell, perturbing DNA synthesis, chromatin organization, and transcription and eventually leading to PARP-dependent cell death. This underlies the synthetic lethality between PARG and ARH3 in cancers and the development of neurodegeneration in ARH3/ADPRHL2-deficient patients. [ABSTRACT FROM AUTHOR]