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Genes & Development Mar 2020Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic... (Review)
Review
Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this review, we focus on the roles of the PARP family members in inflammation and host-pathogen interactions. Here we give an overview the current understanding of the mechanisms by which PARPs promote or suppress proinflammatory activation of macrophages, and various roles PARPs play in virus infections. We also demonstrate how innovative technologies, such as proteomics and systems biology, help to advance this research field and describe unanswered questions.
Topics: ADP-Ribosylation; Host-Pathogen Interactions; Humans; Inflammation; Macrophages; Poly(ADP-ribose) Polymerases; Proteomics; Research; Systems Biology; Virus Diseases
PubMed: 32029454
DOI: 10.1101/gad.334425.119 -
International Journal of Molecular... Oct 2023ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant... (Review)
Review
ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant progress has been made in understanding the mechanism and function of ADP-ribosylation in DNA repair. ADP-ribosylation can regulate the recruitment and activity of DNA repair proteins by facilitating protein-protein interactions and regulating protein conformations. Moreover, ADP-ribosylation can influence additional post-translational modifications (PTMs) of proteins involved in DNA repair, such as ubiquitination, methylation, acetylation, phosphorylation, and SUMOylation. The interaction between ADP-ribosylation and these additional PTMs can fine-tune the activity of DNA repair proteins and ensure the proper execution of the DNA repair process. In addition, PARP inhibitors have been developed as a promising cancer therapeutic strategy by exploiting the dependence of certain cancer types on the PARP-mediated DNA repair pathway. In this paper, we review the progress of ADP-ribosylation in DNA repair, discuss the crosstalk of ADP-ribosylation with additional PTMs in DNA repair, and summarize the progress of PARP inhibitors in cancer therapy.
Topics: Humans; Poly(ADP-ribose) Polymerases; Poly(ADP-ribose) Polymerase Inhibitors; ADP-Ribosylation; DNA Repair; Protein Processing, Post-Translational; Neoplasms; Proteins
PubMed: 37834477
DOI: 10.3390/ijms241915028 -
Molecular Cell Jun 2015Intracellular protein ADP-ribosylation is catalyzed by diphteria toxin-like ADP-ribosyltransferases (ARTDs, formerly PARPs) ("writers"), which use NAD(+) for the...
Intracellular protein ADP-ribosylation is catalyzed by diphteria toxin-like ADP-ribosyltransferases (ARTDs, formerly PARPs) ("writers"), which use NAD(+) for the modification of different amino acids. While some ARTD members catalyze protein poly-ADP-ribosylation, most of them are mono-ADP-ribosyltransferases. ADP-ribosylation is recognized by protein domains ("readers") and reversed by different enzymes ("erasers"). ADP-ribosylation signaling regulates several key cellular processes during health and disease.
Topics: ADP Ribose Transferases; Adenosine Diphosphate Ribose; Biosynthetic Pathways; Humans; Models, Chemical; Molecular Structure; NAD; Niacinamide; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Signal Transduction
PubMed: 26091348
DOI: 10.1016/j.molcel.2015.06.001 -
Chemical Reviews Jul 2023Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can... (Review)
Review
Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can nucleate the formation of these condensates by accelerating the self-association of proteins. Poly(ADP-ribose) (PAR) chains are remarkably transient modifications with turnover rates on the order of minutes, yet they can be required for the formation of granules in response to oxidative stress, DNA damage, and other stimuli. Moreover, accumulation of PAR is linked with adverse phase transitions in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide a primer on how PAR is synthesized and regulated, the diverse structures and chemistries of ADP-ribosylation modifications, and protein-PAR interactions. We review substantial progress in recent efforts to determine the molecular mechanism of PAR-mediated phase separation, and we further delineate how inhibitors of PAR polymerases may be effective treatments for neurodegenerative pathologies. Finally, we highlight the need for rigorous biochemical interrogation of ADP-ribosylation in vivo and in vitro to clarify the exact pathway from PARylation to condensate formation.
Topics: Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Biomolecular Condensates; Poly ADP Ribosylation; Protein Processing, Post-Translational
PubMed: 37115110
DOI: 10.1021/acs.chemrev.2c00851 -
Genes & Development Mar 2020ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life.... (Review)
Review
ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life. Its complexity derives from the varied range of different chemical linkages, including to several amino acid side chains as well as nucleic acids termini and bases, it can adopt. In this review, we provide an overview of the different families of (ADP-ribosyl)hydrolases. We discuss their molecular functions, physiological roles, and influence on human health and disease. Together, the accumulated data support the increasingly compelling view that (ADP-ribosyl)hydrolases are a vital element within ADP-ribosyl signaling pathways and they hold the potential for novel therapeutic approaches as well as a deeper understanding of ADP-ribosylation as a whole.
Topics: ADP-Ribosylation; Adenosine Diphosphate; Humans; Hydrolases; Protein Domains; Structure-Activity Relationship
PubMed: 32029451
DOI: 10.1101/gad.334631.119 -
Amino Acids Jul 2011Arginine adenosine-5'-diphosphoribosylation (ADP-ribosylation) is an enzyme-catalyzed, potentially reversible posttranslational modification, in which the ADP-ribose... (Review)
Review
Arginine adenosine-5'-diphosphoribosylation (ADP-ribosylation) is an enzyme-catalyzed, potentially reversible posttranslational modification, in which the ADP-ribose moiety is transferred from NAD(+) to the guanidino moiety of arginine. At 540 Da, ADP-ribose has the size of approximately five amino acid residues. In contrast to arginine, which, at neutral pH, is positively charged, ADP-ribose carries two negatively charged phosphate moieties. Arginine ADP-ribosylation, thus, causes a notable change in size and chemical property at the ADP-ribosylation site of the target protein. Often, this causes steric interference of the interaction of the target protein with binding partners, e.g. toxin-catalyzed ADP-ribosylation of actin at R177 sterically blocks actin polymerization. In case of the nucleotide-gated P2X7 ion channel, ADP-ribosylation at R125 in the vicinity of the ligand-binding site causes channel gating. Arginine-specific ADP-ribosyltransferases (ARTs) carry a characteristic R-S-EXE motif that distinguishes these enzymes from structurally related enzymes which catalyze ADP-ribosylation of other amino acid side chains, DNA, or small molecules. Arginine-specific ADP-ribosylation can be inhibited by small molecule arginine analogues such as agmatine or meta-iodobenzylguanidine (MIBG), which themselves can serve as targets for arginine-specific ARTs. ADP-ribosylarginine specific hydrolases (ARHs) can restore target protein function by hydrolytic removal of the entire ADP-ribose moiety. In some cases, ADP-ribosylarginine is processed into secondary posttranslational modifications, e.g. phosphoribosylarginine or ornithine. This review summarizes current knowledge on arginine-specific ADP-ribosylation, focussing on the methods available for its detection, its biological consequences, and the enzymes responsible for this modification and its reversal, and discusses future perspectives for research in this field.
Topics: ADP Ribose Transferases; Adenosine Diphosphate Ribose; Amino Acid Sequence; Animals; Arginine; Bacterial Proteins; Conserved Sequence; Humans; Isotope Labeling; Protein Conformation; Protein Processing, Post-Translational; Sequence Alignment; Substrate Specificity
PubMed: 20652610
DOI: 10.1007/s00726-010-0676-2 -
Molecular Cell Nov 2021ADP-ribose (ADPr) readers are essential components of ADP-ribosylation signaling, which regulates genome maintenance and immunity. The identification and discrimination...
ADP-ribose (ADPr) readers are essential components of ADP-ribosylation signaling, which regulates genome maintenance and immunity. The identification and discrimination between monoADPr (MAR) and polyADPr (PAR) readers is difficult because of a lack of suitable affinity-enrichment reagents. We synthesized well-defined ADPr probes and used these for affinity purifications combined with relative and absolute quantitative mass spectrometry to generate proteome-wide MAR and PAR interactomes, including determination of apparent binding affinities. Among the main findings, MAR and PAR readers regulate various common and distinct processes, such as the DNA-damage response, cellular metabolism, RNA trafficking, and transcription. We monitored the dynamics of PAR interactions upon induction of oxidative DNA damage and uncovered the mechanistic connections between ubiquitin signaling and ADP-ribosylation. Taken together, chemical biology enables exploration of MAR and PAR readers using interaction proteomics. Furthermore, the generated MAR and PAR interaction maps significantly expand our current understanding of ADPr signaling.
Topics: ADP-Ribosylation; Adenosine Diphosphate; Adenosine Diphosphate Ribose; Allosteric Site; Animals; Antibodies, Monoclonal; Binding Sites; Biotinylation; Cell Communication; DNA Damage; Genetic Techniques; HeLa Cells; Humans; Mass Spectrometry; Mice; Protein Binding; Protein Processing, Post-Translational; Proteome; Proteomics; Signal Transduction; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 34551281
DOI: 10.1016/j.molcel.2021.08.037 -
Cells Aug 2019Cells constantly adapt their metabolic pathways to meet their energy needs and respond to nutrient availability. During the last two decades, it has become increasingly... (Review)
Review
Cells constantly adapt their metabolic pathways to meet their energy needs and respond to nutrient availability. During the last two decades, it has become increasingly clear that NAD, a coenzyme in redox reactions, also mediates several ubiquitous cell signaling processes. Protein ADP-ribosylation is a post-translational modification that uses NAD as a substrate and is best known as part of the genotoxic stress response. However, there is increasing evidence that NAD-dependent ADP-ribosylation regulates other cellular processes, including metabolic pathways. In this review, we will describe the compartmentalized regulation of NAD biosynthesis, consumption, and regeneration with a particular focus on the role of ADP-ribosylation in the regulation of glucose metabolism in different cellular compartments.
Topics: ADP-Ribosylation; Adenosine Diphosphate Ribose; Animals; Carbohydrate Metabolism; Cell Line; DNA Damage; Glucose; Humans; Metabolic Networks and Pathways; Mice; NAD; Organelles
PubMed: 31412683
DOI: 10.3390/cells8080890 -
Cells Oct 2021The DNA damage response revolves around transmission of information via post-translational modifications, including reversible protein ADP-ribosylation. Here, we applied...
The DNA damage response revolves around transmission of information via post-translational modifications, including reversible protein ADP-ribosylation. Here, we applied a mass-spectrometry-based Af1521 enrichment technology for the identification and quantification of ADP-ribosylation sites as a function of various DNA damage stimuli and time. In total, we detected 1681 ADP-ribosylation sites residing on 716 proteins in U2OS cells and determined their temporal dynamics after exposure to the genotoxins HO and MMS. Intriguingly, we observed a widespread but low-abundance serine ADP-ribosylation response at the earliest time point, with later time points centered on increased modification of the same sites. This suggests that early serine ADP-ribosylation events may serve as a platform for an integrated signal response. While treatment with HO and MMS induced homogenous ADP-ribosylation responses, we observed temporal differences in the ADP-ribosylation site abundances. Exposure to MMS-induced alkylating stress induced the strongest ADP-ribosylome response after 30 min, prominently modifying proteins involved in RNA processing, whereas in response to HO-induced oxidative stress ADP-ribosylation peaked after 60 min, mainly modifying proteins involved in DNA damage pathways. Collectively, the dynamic ADP-ribosylome presented here provides a valuable insight into the temporal cellular regulation of ADP-ribosylation in response to DNA damage.
Topics: ADP-Ribosylation; Cell Line, Tumor; DNA Damage; Humans; Hydrogen Peroxide; Methyl Methanesulfonate; Signal Transduction; Time Factors
PubMed: 34831150
DOI: 10.3390/cells10112927 -
Current Opinion in Genetics &... Dec 2021PARP1 and PARP2 govern the DNA-damage response by catalysing the reversible post-translational modification ADP-ribosylation. During the repair of DNA lesions, PARP1 and... (Review)
Review
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.
Topics: ADP-Ribosylation; Carrier Proteins; DNA; DNA Damage; Humans; Nuclear Proteins; Serine
PubMed: 34340015
DOI: 10.1016/j.gde.2021.07.005