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Pathogens (Basel, Switzerland) Feb 2023Adenosine diphosphate (ADP)-ribosylation is a reversible post-translational modification catalyzed by ADP-ribosyltransferases (ARTs). ARTs transfer one or more... (Review)
Review
Adenosine diphosphate (ADP)-ribosylation is a reversible post-translational modification catalyzed by ADP-ribosyltransferases (ARTs). ARTs transfer one or more ADP-ribose from nicotinamide adenine dinucleotide (NAD) to the target substrate and release the nicotinamide (Nam). Accordingly, it comes in two forms: mono-ADP-ribosylation (MARylation) and poly-ADP-ribosylation (PARylation). ADP-ribosylation plays important roles in many biological processes, such as DNA damage repair, gene regulation, and energy metabolism. Emerging evidence demonstrates that ADP-ribosylation is implicated in host antiviral immune activity. Here, we summarize and discuss ADP-ribosylation modifications that occur on both host and viral proteins and their roles in host antiviral response.
PubMed: 36839575
DOI: 10.3390/pathogens12020303 -
Nature Reviews. Molecular Cell Biology Jan 2024
Topics: ADP-Ribosylation; Poly(ADP-ribose) Polymerases; Adenosine Diphosphate Ribose
PubMed: 37344632
DOI: 10.1038/s41580-023-00630-x -
Molecular Cell Feb 2024Nucleosomes, the basic structural units of chromatin, hinder recruitment and activity of various DNA repair proteins, necessitating modifications that enhance DNA...
Nucleosomes, the basic structural units of chromatin, hinder recruitment and activity of various DNA repair proteins, necessitating modifications that enhance DNA accessibility. Poly(ADP-ribosyl)ation (PARylation) of proteins near damage sites is an essential initiation step in several DNA-repair pathways; however, its effects on nucleosome structural dynamics and organization are unclear. Using NMR, cryoelectron microscopy (cryo-EM), and biochemical assays, we show that PARylation enhances motions of the histone H3 tail and DNA, leaving the configuration of the core intact while also stimulating nuclease digestion and ligation of nicked nucleosomal DNA by LIG3. PARylation disrupted interactions between nucleosomes, preventing self-association. Addition of LIG3 and XRCC1 to PARylated nucleosomes generated condensates that selectively partition DNA repair-associated proteins in a PAR- and phosphorylation-dependent manner in vitro. Our results establish that PARylation influences nucleosomes across different length scales, extending from the atom-level motions of histone tails to the mesoscale formation of condensates with selective compositions.
Topics: Nucleosomes; Poly ADP Ribosylation; Poly(ADP-ribose) Polymerases; Cryoelectron Microscopy; Biomolecular Condensates; DNA Repair; Histones; DNA; DNA Damage; Poly (ADP-Ribose) Polymerase-1
PubMed: 38215753
DOI: 10.1016/j.molcel.2023.12.019 -
Cell Reports Sep 2023The timely removal of ADP-ribosylation is crucial for efficient DNA repair. However, much remains to be discovered about ADP-ribosylhydrolases. Here, we characterize the...
The timely removal of ADP-ribosylation is crucial for efficient DNA repair. However, much remains to be discovered about ADP-ribosylhydrolases. Here, we characterize the physiological role of TARG1, an ADP-ribosylhydrolase that removes aspartate/glutamate-linked ADP-ribosylation. We reveal its function in the DNA damage response and show that the loss of TARG1 sensitizes cells to inhibitors of topoisomerase II, ATR, and PARP. Furthermore, we find a PARP1-mediated synthetic lethal interaction between TARG1 and PARG, driven by the toxic accumulation of ADP-ribosylation, that induces replication stress and genomic instability. Finally, we show that histone PARylation factor 1 (HPF1) deficiency exacerbates the toxicity and genomic instability induced by excessive ADP-ribosylation, suggesting a close crosstalk between components of the serine- and aspartate/glutamate-linked ADP-ribosylation pathways. Altogether, our data identify TARG1 as a potential biomarker for the response of cancer cells to PARP and PARG inhibition and establish that the interplay of TARG1 and PARG protects cells against genomic instability.
Topics: Humans; Poly(ADP-ribose) Polymerase Inhibitors; Aspartic Acid; ADP-Ribosylation; Genomic Instability; Glutamates; Carrier Proteins; Nuclear Proteins
PubMed: 37676774
DOI: 10.1016/j.celrep.2023.113113 -
Experimental and Therapeutic Medicine Jun 2021The current knowledge regarding ADP-ribosylation modifications of histones, particularly mono-ADP-ribosylation modifications, is limited. However, recent studies have... (Review)
Review
The current knowledge regarding ADP-ribosylation modifications of histones, particularly mono-ADP-ribosylation modifications, is limited. However, recent studies have identified an increasing number of mono-ADP-ribosyltransferases and the role of mono-ADP-ribosylation has become a hot research topic. In particular, histones that are substrates of several mono-ADP-ribosyltransferases and mono-ADP-ribosylated histones were indicated to be involved in numerous physiological or pathological processes. Compared to poly-ADP-ribosylation histone modification, the use of mono-ADP-ribosylation histone modification is restricted by the limited methods for research into its function in physiological or pathological processes. The aim of the present review was to discuss the details regarding mono-ADP-ribosylation modification of histones and the currently known functions thereof, such as cell physiological and pathological processes, including tumorigenesis.
PubMed: 33850549
DOI: 10.3892/etm.2021.10009 -
Immunology Sep 2021ADP-ribosylation is the addition of one or more (up to some hundreds) ADP-ribose moieties to acceptor proteins. This evolutionary ancient post-translational modification... (Review)
Review
ADP-ribosylation is the addition of one or more (up to some hundreds) ADP-ribose moieties to acceptor proteins. This evolutionary ancient post-translational modification (PTM) is involved in fundamental processes including DNA repair, inflammation, cell death, differentiation and proliferation, among others. ADP-ribosylation is catalysed by two major families of enzymes: the cholera toxin-like ADP-ribosyltransferases (ARTCs) and the diphtheria toxin-like ADP-ribosyltransferases (ARTDs, also known as PARPs). ARTCs sense and use extracellular NAD, which may represent a danger signal, whereas ARTDs are present in the cell nucleus and/or cytoplasm. ARTCs mono-ADP-ribosylate their substrates, whereas ARTDs, according to the specific family member, are able to mono- or poly-ADP-ribosylate target proteins or are devoid of enzymatic activity. Both mono- and poly-ADP-ribosylation are dynamic processes, as specific hydrolases are able to remove single or polymeric ADP moieties. This dynamic equilibrium between addition and degradation provides plasticity for fast adaptation, a feature being particularly relevant to immune cell functions. ADP-ribosylation regulates differentiation and functions of myeloid, T and B cells. It also regulates the expression of cytokines and chemokines, production of antibodies, isotype switch and the expression of several immune mediators. Alterations in these processes involve ADP-ribosylation in virtually any acute and chronic inflammatory/immune-mediated disease. Besides, pathogens developed mechanisms to contrast the action of ADP-ribosylating enzymes by using their own hydrolases and/or to exploit this PTM to sustain their virulence. In the present review, we summarize and discuss recent findings on the role of ADP-ribosylation in immunobiology, immune evasion/subversion by pathogens and immune-mediated diseases.
Topics: ADP-Ribosylation; Alarmins; Animals; Humans; Immune Evasion; Immunity, Cellular; Immunization; Inflammation; Virulence; Virus Diseases
PubMed: 33783820
DOI: 10.1111/imm.13332 -
Trends in Microbiology Sep 2021The poly(ADP-ribose) polymerases (PARPs) family contains 17 members in humans, sharing a PARP domain to transfer ADP-ribose groups to target proteins to trigger... (Review)
Review
The poly(ADP-ribose) polymerases (PARPs) family contains 17 members in humans, sharing a PARP domain to transfer ADP-ribose groups to target proteins to trigger ADP-ribosylation. The roles of PARPs have evolved from DNA damage repair to diverse biological processes, such as gene transcription, cellular stress response, etc. Recently, seminal studies have demonstrated the critical roles of PAPRs in antiviral innate immunity. PARPs catalyze ADP-ribosylation, a fundamental post-translational modification, using NAD as a substrate. ADP-ribosylation can occur either as mono- or poly-(ADP-ribosyl)ation, which is initially linked to DNA damage repair, as exemplified by PARP1. Recent advances in host antiviral immunity demonstrated that several PARPs, such as PARP9, 11, 12, 13, 14, etc., have broad-spectrum antiviral activities that are independent of their ADP-ribosylation.
Topics: ADP-Ribosylation; Animals; Humans; Multigene Family; Poly(ADP-ribose) Polymerases; Virus Diseases; Virus Physiological Phenomena; Viruses
PubMed: 33483164
DOI: 10.1016/j.tim.2021.01.002 -
Molecular Cell Jul 2023Modification of nucleic acids by ADP-ribosylation is catalyzed by various ADP-ribosyltransferases, including the DarT enzyme. The latter is part of the bacterial...
Modification of nucleic acids by ADP-ribosylation is catalyzed by various ADP-ribosyltransferases, including the DarT enzyme. The latter is part of the bacterial toxin-antitoxin (TA) system DarTG, which was shown to provide control of DNA replication and bacterial growth as well as protection against bacteriophages. Two subfamilies have been identified, DarTG1 and DarTG2, which are distinguished by their associated antitoxins. While DarTG2 catalyzes reversible ADP-ribosylation of thymidine bases employing a macrodomain as antitoxin, the DNA ADP-ribosylation activity of DarTG1 and the biochemical function of its antitoxin, a NADAR domain, are as yet unknown. Using structural and biochemical approaches, we show that DarT1-NADAR is a TA system for reversible ADP-ribosylation of guanosine bases. DarT1 evolved the ability to link ADP-ribose to the guanine amino group, which is specifically hydrolyzed by NADAR. We show that guanine de-ADP-ribosylation is also conserved among eukaryotic and non-DarT-associated NADAR members, indicating a wide distribution of reversible guanine modifications beyond DarTG systems.
Topics: Guanosine; ADP-Ribosylation; ADP Ribose Transferases; Eukaryotic Cells; Antitoxins; Adenosine Diphosphate Ribose
PubMed: 37390817
DOI: 10.1016/j.molcel.2023.06.013 -
Frontiers in Cell and Developmental... 2022ADP-ribosylation is a reversible post-translational modification (PTM) tightly regulated by the dynamic interplay between its writers, readers and erasers. As an... (Review)
Review
ADP-ribosylation is a reversible post-translational modification (PTM) tightly regulated by the dynamic interplay between its writers, readers and erasers. As an intricate and versatile PTM, ADP-ribosylation plays critical roles in various physiological and pathological processes. In this review, we discuss the major players involved in the ADP-ribosylation cycle, which may facilitate the investigation of the ADP-ribosylation function and contribute to the understanding and treatment of ADP-ribosylation associated disease.
PubMed: 36035988
DOI: 10.3389/fcell.2022.941356 -
Cellular and Molecular Life Sciences :... Feb 2023Replication of viruses requires interaction with host cell factors and repression of innate immunity. Recent findings suggest that a subset of intracellular...
Replication of viruses requires interaction with host cell factors and repression of innate immunity. Recent findings suggest that a subset of intracellular mono-ADP-ribosylating PARPs, which are induced by type I interferons, possess antiviral activity. Moreover, certain RNA viruses, including Chikungunya virus (CHIKV), encode mono-ADP-ribosylhydrolases. Together, this suggests a role for mono-ADP-ribosylation (MARylation) in host-virus conflicts, but the relevant substrates have not been identified. We addressed which PARP restricts CHIKV replication and identified PARP10 and PARP12. For PARP10, this restriction was dependent on catalytic activity. Replication requires processing of the non-structural polyprotein nsP1-4 by the protease located in nsP2 and the assembly of the four individual nsP1-nsP4 into a functional replication complex. PARP10 and PARP12 inhibited the production of nsP3, indicating a defect in polyprotein processing. The nsP3 protein encodes a macrodomain with de-MARylation activity, which is essential for replication. In support for MARylation affecting polyprotein processing, de-MARylation defective CHIKV replicons revealed reduced production of nsP2 and nsP3. We hypothesized that MARylation regulates the proteolytic function of nsP2. Indeed, we found that nsP2 is MARylated by PARP10 and, as a consequence, its proteolytic activity was inhibited. NsP3-dependent de-MARylation reactivated the protease. Hence, we propose that PARP10-mediated MARylation prevents polyprotein processing and consequently virus replication. Together, our findings provide a mechanistic explanation for the role of the viral MAR hydrolase in CHIKV replication.
Topics: ADP-Ribosylation; Chikungunya virus; Peptide Hydrolases; Polyproteins; Viral Nonstructural Proteins; Virus Replication; Poly(ADP-ribose) Polymerases
PubMed: 36840772
DOI: 10.1007/s00018-023-04717-8