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Biochemical Society Transactions Aug 2021The COVID-19 pandemic has prompted intense research efforts into elucidating mechanisms of coronavirus pathogenesis and to propose antiviral interventions. The... (Review)
Review
The COVID-19 pandemic has prompted intense research efforts into elucidating mechanisms of coronavirus pathogenesis and to propose antiviral interventions. The interferon (IFN) response is the main antiviral component of human innate immunity and is actively suppressed by several non-structural SARS-CoV-2 proteins, allowing viral replication within human cells. Differences in IFN signalling efficiency and timing have emerged as central determinants of the variability of COVID-19 disease severity between patients, highlighting the need for an improved understanding of host-pathogen interactions that affect the IFN response. ADP-ribosylation is an underexplored post-translational modification catalyzed by ADP-ribosyl transferases collectively termed poly(ADP-ribose) polymerases (PARPs). Several human PARPs are induced by the IFN response and participate in antiviral defences by regulating IFN signalling itself, modulating host processes such as translation and protein trafficking, as well as directly modifying and inhibiting viral target proteins. SARS-CoV-2 and other viruses encode a macrodomain that hydrolyzes ADP-ribose modifications, thus counteracting antiviral PARP activity. This mini-review provides a brief overview of the known targets of IFN-induced ADP-ribosylation and the functions of viral macrodomains, highlighting several open questions in the field.
Topics: ADP-Ribosylation; COVID-19; Host-Pathogen Interactions; Humans; Poly(ADP-ribose) Polymerases; SARS-CoV-2
PubMed: 34351418
DOI: 10.1042/BST20201212 -
The Journal of Biological Chemistry Nov 2023O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, a prevalent protein post-translational modification (PTM) that occurs intracellularly, has been shown to crosstalk...
O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, a prevalent protein post-translational modification (PTM) that occurs intracellularly, has been shown to crosstalk with phosphorylation and ubiquitination. However, it is unclear whether it interplays with other PTMs. Here we studied its relationship with ADP-ribosylation, which involves decorating target proteins with the ADP-ribose moiety. We discovered that the poly(ADP-ribosyl)ation "eraser", ADP-ribose glycohydrolase (PARG), is O-GlcNAcylated at Ser26, which is in close proximity to its nuclear localization signal. O-GlcNAcylation of PARG promotes nuclear localization and chromatin association. Upon DNA damage, O-GlcNAcylation augments the recruitment of PARG to DNA damage sites and interacting with proliferating cell nuclear antigen (PCNA). In hepatocellular carcinoma (HCC) cells, PARG O-GlcNAcylation enhances the poly(ADP-ribosyl)ation of DNA damage-binding protein 1 (DDB1) and attenuates its auto-ubiquitination, thereby stabilizing DDB1 and allowing it to degrade its downstream targets, such as c-Myc. We further demonstrated that PARG-S26A, the O-GlcNAc-deficient mutant, promoted HCC in mouse xenograft models. Our findings thus reveal that PARG O-GlcNAcylation inhibits HCC, and we propose that O-GlcNAc glycosylation may crosstalk with many other PTMs.
Topics: Animals; Humans; Mice; Acetylglucosamine; ADP-Ribosylation; Carcinoma, Hepatocellular; Glycoside Hydrolases; Liver Neoplasms; Poly Adenosine Diphosphate Ribose; Glycosylation; Protein Processing, Post-Translational
PubMed: 37858678
DOI: 10.1016/j.jbc.2023.105354 -
Proceedings of the National Academy of... Mar 2023Poly(ADP-ribose) polymerase-1 (PARP1) has been reported to play an important role in longevity. Here, we showed that the knockdown of the PARP1 extended the lifespan of...
Poly(ADP-ribose) polymerase-1 (PARP1) has been reported to play an important role in longevity. Here, we showed that the knockdown of the PARP1 extended the lifespan of , with particular emphasis on the skeletal muscle. The muscle-specific mutant exhibited resistance to starvation and oxidative stress, as well as an increased ability to climb, with enhanced mitochondrial biogenesis and activity at an older age. Mechanistically, the inhibition of PARP1 increases the activity of AMP-activated protein kinase alpha (AMPKα) and mitochondrial turnover. PARP1 could interact with AMPKα and then regulate it via poly(ADP ribosyl)ation (PARylation) at residues E155 and E195. Double knockdown of PARP1 and AMPKα, specifically in muscle, could counteract the effects of PARP1 inhibition in . Finally, we showed that increasing lifespan via maintaining mitochondrial network homeostasis required intact PTEN induced kinase 1 (PINK1). Taken together, these data indicate that the interplay between PARP1 and AMPKα can manipulate mitochondrial turnover, and be targeted to promote longevity.
Topics: Animals; AMP-Activated Protein Kinases; Drosophila; Drosophila Proteins; Longevity; Muscles; Poly (ADP-Ribose) Polymerase-1; Poly ADP Ribosylation; Protein Serine-Threonine Kinases
PubMed: 36947517
DOI: 10.1073/pnas.2213857120 -
Nature Sep 2022Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional...
Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation. Here we show that promoters are protected from oxidative damage via a process mediated by the nuclear mitotic apparatus protein NuMA (also known as NUMA1). NuMA exhibits genomic occupancy approximately 100 bp around transcription start sites. It binds the initiating form of RNA polymerase II, pause-release factors and single-strand break repair (SSBR) components such as TDP1. The binding is increased on chromatin following oxidative damage, and TDP1 enrichment at damaged chromatin is facilitated by NuMA. Depletion of NuMA increases oxidative damage at promoters. NuMA promotes transcription by limiting the polyADP-ribosylation of RNA polymerase II, increasing its availability and release from pausing at promoters. Metabolic labelling of nascent RNA identifies genes that depend on NuMA for transcription including immediate-early response genes. Complementation of NuMA-deficient cells with a mutant that mediates binding to SSBR, or a mitotic separation-of-function mutant, restores SSBR defects. These findings underscore the importance of oxidative DNA damage repair at gene regulatory elements and describe a process that fulfils this function.
Topics: Cell Cycle Proteins; Chromatin; DNA Damage; DNA Repair; Genes; Genetic Complementation Test; Mitosis; Mutation; Oxidative Stress; Phosphoric Diester Hydrolases; Poly ADP Ribosylation; Promoter Regions, Genetic; RNA; RNA Polymerase II; Spindle Apparatus; Transcription Initiation Site
PubMed: 36171374
DOI: 10.1038/s41586-022-05217-8 -
Methods in Molecular Biology (Clifton,... 2018Synthetic mono-ADPr-peptides are useful for structural, biochemical, and proteomics studies. We describe here a protocol for the preparation of mono-ADPr-peptides based...
Synthetic mono-ADPr-peptides are useful for structural, biochemical, and proteomics studies. We describe here a protocol for the preparation of mono-ADPr-peptides based on a fairly standard Fmoc-based solid-phase synthesis. Phosphoribosylated precursor building blocks are introduced into the peptide chain on solid-phase and subsequently converted to ADPr-sites by chemical phosphorylation with adenosine phosphoramidite. Suitably protected phosphoribosylated glutamine, asparagine, and citrulline building blocks described in this protocol allow introduction of ADP-Gln, ADPr-Asn, and ADPr-Cit into peptide chains as demonstrated for three peptides. Trifunctional amino acids, for which base-sensitive side-chain protection is available, can be accommodated in the sequences flanking the ADPr-cites.
Topics: ADP-Ribosylation; Adenosine Diphosphate Ribose; Amino Acids; Asparagine; Fluorenes; Glutamine; Peptide Biosynthesis; Phosphorylation; Solid-Phase Synthesis Techniques
PubMed: 30097880
DOI: 10.1007/978-1-4939-8588-3_24 -
Viruses Jan 2023ADP-ribosylation (ADPRylation) is a versatile posttranslational modification in eukaryotic cells which is involved in the regulation of a wide range of key biological...
ADP-ribosylation (ADPRylation) is a versatile posttranslational modification in eukaryotic cells which is involved in the regulation of a wide range of key biological processes, including DNA repair, cell signalling, programmed cell death, growth and development and responses to biotic and abiotic stresses. Members of the poly(ADP-ribosyl) polymerase (PARP) family play a central role in the process of ADPRylation. Protein targets can be modified by adding either a single ADP-ribose moiety (mono(ADP-ribosyl)ation; MARylation), which is catalysed by mono(ADP-ribosyl) transferases (MARTs or PARP "monoenzymes"), or targets may be decorated with chains of multiple ADP-ribose moieties (PARylation), via the activities of PARP "polyenzymes". Studies have revealed crosstalk between PARylation (and to a lesser extent, MARylation) processes in plants and plant-virus interactions, suggesting that these tight links may represent a novel factor regulating plant antiviral immunity. From this perspective, we go through the literature linking PARylation-associated processes with other plant regulation pathways controlling virus resistance. Once unraveled, these links may serve as the basis of innovative strategies to improve crop resistance to viruses under challenging environmental conditions which could mitigate yield losses.
Topics: Poly(ADP-ribose) Polymerases; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; ADP-Ribosylation; Adenosine Diphosphate Ribose; Antiviral Agents
PubMed: 36680280
DOI: 10.3390/v15010241 -
Journal of the American Chemical Society Jun 2023We report here chemoenzymatic and fully synthetic methodologies to modify aspartate and glutamate side chains with ADP-ribose at specific sites on peptides. Structural...
We report here chemoenzymatic and fully synthetic methodologies to modify aspartate and glutamate side chains with ADP-ribose at specific sites on peptides. Structural analysis of aspartate and glutamate ADP-ribosylated peptides reveals near-quantitative migration of the side chain linkage from the anomeric carbon to the 2″- or 3″-ADP-ribose hydroxyl moieties. We find that this linkage migration pattern is unique to aspartate and glutamate ADP-ribosylation and propose that the observed isomer distribution profile is present in biochemical and cellular environments. After defining distinct stability properties of aspartate and glutamate ADP-ribosylation, we devise methods to install homogenous ADP-ribose chains at specific glutamate sites and assemble glutamate-modified peptides into full-length proteins. By implementing these technologies, we show that histone H2B E2 tri-ADP-ribosylation is able to stimulate the chromatin remodeler ALC1 with similar efficiency to histone serine ADP-ribosylation. Our work reveals fundamental principles of aspartate and glutamate ADP-ribosylation and enables new strategies to interrogate the biochemical consequences of this widespread protein modification.
Topics: Aspartic Acid; Glutamic Acid; ADP-Ribosylation; Histones; Adenosine Diphosphate Ribose; Peptides
PubMed: 37315125
DOI: 10.1021/jacs.3c03771 -
Ageing Research Reviews Feb 2024ADP-ribosylation (ADPr) is a dynamically reversible post-translational modification (PTM) driven primarily by ADP-ribosyltransferases (ADPRTs or ARTs), which have... (Review)
Review
ADP-ribosylation (ADPr) is a dynamically reversible post-translational modification (PTM) driven primarily by ADP-ribosyltransferases (ADPRTs or ARTs), which have ADP-ribosyl transfer activity. ADPr modification is involved in signaling pathways, DNA damage repair, metabolism, immunity, and inflammation. In recent years, several studies have revealed that new targets or treatments for tumors, cardiovascular diseases, neuromuscular diseases and infectious diseases can be explored by regulating ADPr. Here, we review the recent research progress on ART-mediated ADP-ribosylation and the latest findings in the diagnosis and treatment of related diseases.
Topics: Humans; ADP-Ribosylation; ADP Ribose Transferases; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 38141734
DOI: 10.1016/j.arr.2023.102176 -
Cancer Cell Jun 2018Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite...
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.
Topics: Animals; BRCA1 Protein; Breast Neoplasms; Cell Line, Tumor; Female; Glycoside Hydrolases; Homologous Recombination; Humans; Mice, 129 Strain; Mice, Knockout; Ovarian Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly ADP Ribosylation; Poly(ADP-ribose) Polymerase Inhibitors; Synthetic Lethal Mutations
PubMed: 29894693
DOI: 10.1016/j.ccell.2018.05.008 -
Biochemical Society Transactions Jun 2023ADP-ribosylation is a post-translational modification involved in DNA damage response (DDR). In higher organisms it is synthesised by PARP 1-3, DNA strand break sensors....
ADP-ribosylation is a post-translational modification involved in DNA damage response (DDR). In higher organisms it is synthesised by PARP 1-3, DNA strand break sensors. Recent advances have identified serine residues as the most common targets for ADP-ribosylation during DDR. To ADP-ribosylate serine, PARPs require an accessory factor, HPF1 which completes the catalytic domain. Through ADP-ribosylation, PARPs recruit a variety of factors to the break site and control their activities. However, the timely removal of ADP-ribosylation is also key for genome stability and is mostly performed by two hydrolases: PARG and ARH3. Here, we describe the key writers, readers and erasers of ADP-ribosylation and their contribution to the mounting of the DDR. We also discuss the use of PARP inhibitors in cancer therapy and the ways to tackle PARPi treatment resistance.
Topics: ADP-Ribosylation; DNA Damage; Protein Processing, Post-Translational; Hydrolases; Serine
PubMed: 37171085
DOI: 10.1042/BST20220749