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Molecular Cell May 2023PARPs catalyze ADP-ribosylation-a post-translational modification that plays crucial roles in biological processes, including DNA repair, transcription, immune... (Review)
Review
PARPs catalyze ADP-ribosylation-a post-translational modification that plays crucial roles in biological processes, including DNA repair, transcription, immune regulation, and condensate formation. ADP-ribosylation can be added to a wide range of amino acids with varying lengths and chemical structures, making it a complex and diverse modification. Despite this complexity, significant progress has been made in developing chemical biology methods to analyze ADP-ribosylated molecules and their binding proteins on a proteome-wide scale. Additionally, high-throughput assays have been developed to measure the activity of enzymes that add or remove ADP-ribosylation, leading to the development of inhibitors and new avenues for therapy. Real-time monitoring of ADP-ribosylation dynamics can be achieved using genetically encoded reporters, and next-generation detection reagents have improved the precision of immunoassays for specific forms of ADP-ribosylation. Further development and refinement of these tools will continue to advance our understanding of the functions and mechanisms of ADP-ribosylation in health and disease.
Topics: Poly(ADP-ribose) Polymerases; ADP-Ribosylation; Protein Processing, Post-Translational; Adenosine Diphosphate Ribose
PubMed: 37119811
DOI: 10.1016/j.molcel.2023.04.009 -
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 -
The Journal of Clinical Investigation Jun 2023The ADP ribosyltransferases (PARPs 1-17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze...
The ADP ribosyltransferases (PARPs 1-17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cyclic GMP-AMP synthase (cGAS) expression, and type I IFN production during TB. Thus, Parp9-deficient mice were susceptible to Mycobacterium tuberculosis infection and exhibited increased TB disease, cGAS and 2'3'-cyclic GMP-AMP (cGAMP) expression, and type I IFN production, along with upregulation of complement and coagulation pathways. Enhanced M. tuberculosis susceptibility is type I IFN dependent, as blockade of IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility of Parp9-/- mice. Thus, in sharp contrast to PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB.
Topics: Animals; Humans; Mice; ADP-Ribosylation; DNA Repair; Mycobacterium tuberculosis; Nucleotidyltransferases; Poly(ADP-ribose) Polymerases; Tuberculosis
PubMed: 37200107
DOI: 10.1172/JCI158630 -
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 -
Ageing Research Reviews Jul 2024Aging, a complex biological process, plays key roles the development of multiple disorders referred as aging-related diseases involving cardiovascular diseases, stroke,... (Review)
Review
Aging, a complex biological process, plays key roles the development of multiple disorders referred as aging-related diseases involving cardiovascular diseases, stroke, neurodegenerative diseases, cancers, lipid metabolism-related diseases. ADP-ribosylation is a reversible modification onto proteins and nucleic acids to alter their structures and/or functions. Growing evidence support the importance of ADP-ribosylation and ADP-ribosylation-associated enzymes in aging and age-related diseases. In this review, we summarized ADP-ribosylation-associated proteins including ADP-ribosyl transferases, the ADP-ribosyl hydrolyses and ADP-ribose binding domains. Furthermore, we outlined the latest knowledge about regulation of ADP-ribosylation in the pathogenesis and progression of main aging-related diseases, organism aging and cellular senescence, and we also speculated the underlying mechanisms to better disclose this novel molecular network. Moreover, we discussed current issues and provided an outlook for future research, aiming to revealing the unknown bio-properties of ADP-ribosylation, and establishing a novel therapeutic perspective in aging-related diseases and health aging via targeting ADP-ribosylation.
Topics: Humans; Aging; ADP-Ribosylation; Animals; Cellular Senescence; Neurodegenerative Diseases
PubMed: 38815933
DOI: 10.1016/j.arr.2024.102347 -
Methods in Molecular Biology (Clifton,... 2021ADP-ribosylation is a widespread reversible chemical modification of macromolecular targets. Protein ADP-ribosylation has been widely studied and plays a vital role in...
ADP-ribosylation is a widespread reversible chemical modification of macromolecular targets. Protein ADP-ribosylation has been widely studied and plays a vital role in the regulation of several biological processes. In recent years there has been increasing interest in alternative ADP-ribosylation targets such as nucleic acids-DNA and RNA. Here we report different methods to detect ADP-ribosylation of RNA substrates.
Topics: ADP-Ribosylation; DNA; Poly(ADP-ribose) Polymerases; RNA
PubMed: 34085249
DOI: 10.1007/978-1-0716-1374-0_15 -
Methods in Molecular Biology (Clifton,... 2023Immunoprecipitation is an essential methodology for enriching and purifying targeted proteins and peptides for in-depth analysis by any number of further techniques,...
Immunoprecipitation is an essential methodology for enriching and purifying targeted proteins and peptides for in-depth analysis by any number of further techniques, from Western blotting to mass spectrometry (MS). Historically, the posttranslational modification ADP-ribosylation (ADPr) has been studied mainly in its polymerized form (poly-ADPr), but recent studies support the abundance and physiological relevance of mono-ADPr. Here, we describe several approaches to enrich mono-ADP-ribosylated proteins and peptides using mono-ADPr-specific antibodies, which can be tailored to a desired target and mode of downstream analysis.
Topics: ADP-Ribosylation; Protein Processing, Post-Translational; Immunoprecipitation; Proteins; Peptides; Antibodies
PubMed: 36515834
DOI: 10.1007/978-1-0716-2891-1_9 -
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 -
Current Protein & Peptide Science 2016ADP-ribosylation describes an ancient and highly conserved posttranslational modification (PTM) of proteins. Many cellular processes have been identified that are... (Review)
Review
ADP-ribosylation describes an ancient and highly conserved posttranslational modification (PTM) of proteins. Many cellular processes have been identified that are regulated by ADP-ribosylation, including DNA repair, gene transcription and signaling processes. Enzymes catalyzing ADP-ribosylation use NAD+ as a cofactor to transfer ADP-ribose to a substrate under release of nicotinamide. In mammals extracellular and intracellular enzymes have been described. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs) and some Sirtuins. Extracellular and intracellular ARTs belong to the cholera toxin-like (ARTC) and the diphtheria toxin-like (ARTD) subclass, respectively. ARTDs can be further subdivided depending on their ability to either generate poly-ADP-ribose chains, or to mono-ADP-ribosylate substrates. Similar to the latter, ARTCs and Sirtuins are restricted to mono-ADP-ribosylation. Recent findings have provided information about the functional consequences of ADP-ribosylation. Analogous to other PTMs, ADP-ribosylation can exert allosteric effects on enzymes, thereby controlling their catalytic activity. Moreover, this PTM can be read by multiple protein motifs and domains mediating protein-protein interactions. Typically these readers can distinguish between mono- and poly-ADP-ribosylation. Furthermore, with the description of proteins that can erase ADP-ribosylation, this posttranslational modification is fully reversible and thus provides an additional mechanism to transiently control protein functions and networks. In this review we will describe the most recent findings on motifs and domains that are related to ADP-ribosylation processes with a particular focus on readers and erasers. These new findings provide evidence for broad functional roles of ADP-ribosylation and a high diversity of mechanisms that contribute to the downstream consequences of this modification.
Topics: ADP Ribose Transferases; Adenosine Diphosphate; Adenosine Diphosphate Ribose; Animals; Glycosylation; Humans; Multigene Family; Phosphoric Monoester Hydrolases; Poly(ADP-ribose) Polymerases; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Sirtuins
PubMed: 27090904
DOI: 10.2174/1389203717666160419144846