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Mutation Research. Reviews in Mutation... 2019Poly(ADP-ribosyl)ation (aka PARylation) is a unique protein post-translational modification (PTM) first described over 50 years ago. PARylation regulates a number of... (Review)
Review
Poly(ADP-ribosyl)ation (aka PARylation) is a unique protein post-translational modification (PTM) first described over 50 years ago. PARylation regulates a number of biological processes including chromatin remodeling, the DNA damage response (DDR), transcription, apoptosis, and mitosis. The subsequent discovery of poly(ADP-ribose) polymerase-1 (PARP-1) catalyzing DNA-dependent PARylation spearheaded the field of DDR. The expanding knowledge about the poly ADP-ribose (PAR) recognition domains prompted the discovery of novel DDR factors and revealed crosstalk with other protein PTMs including phosphorylation, ubiquitination, methylation and acetylation. In this review, we highlight the current knowledge on PAR-regulated DDR, PAR recognition domain, and PARP inhibition in cancer therapy.
Topics: Animals; DNA Damage; DNA Repair; Humans; Neoplasms; Poly ADP Ribosylation; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 31395352
DOI: 10.1016/j.mrrev.2017.09.004 -
Nucleic Acids Research Sep 2022RNA function relies heavily on posttranscriptional modifications. Recently, it was shown that certain PARPs and TRPT1 can ADP-ribosylate RNA in vitro. Traditionally,...
RNA function relies heavily on posttranscriptional modifications. Recently, it was shown that certain PARPs and TRPT1 can ADP-ribosylate RNA in vitro. Traditionally, intracellular ADP-ribosylation has been considered mainly as a protein posttranslational modification. To date, it is not clear whether RNA ADP-ribosylation occurs in cells. Here we present evidence that different RNA species are ADP-ribosylated in human cells. The modification of cellular RNA is mediated by several transferases such as TRPT1, PARP10, PARP11, PARP12 and PARP15 and is counteracted by different hydrolases including TARG1, PARG and ARH3. In addition, diverse cellular stressors can modulate the content of ADP-ribosylated RNA in cells. We next investigated potential consequences of ADP-ribosylation for RNA and found that ADPr-capped mRNA is protected against XRN1 mediated degradation but is not translated. T4 RNA ligase 1 can ligate ADPr-RNA in absence of ATP, resulting in the incorporation of an abasic site. We thus provide the first evidence of RNA ADP-ribosylation in mammalian cells and postulate potential functions of this novel RNA modification.
Topics: Animals; Humans; RNA; ADP-Ribosylation; Protein Processing, Post-Translational; Hydrolases; Adenosine Diphosphate; Adenosine Diphosphate Ribose; Mammals; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins
PubMed: 36018800
DOI: 10.1093/nar/gkac711 -
Trends in Genetics : TIG Aug 2019A central and causative feature of age-related neurodegenerative disease is the deposition of misfolded proteins in the brain. To devise novel approaches to treatment,... (Review)
Review
A central and causative feature of age-related neurodegenerative disease is the deposition of misfolded proteins in the brain. To devise novel approaches to treatment, regulatory pathways that modulate these aggregation-prone proteins must be defined. One such pathway is post-translational modification by the addition of poly(ADP-ribose) (PAR), which promotes protein recruitment and localization in several cellular contexts. Mounting evidence implicates PAR in seeding the abnormal localization and accumulation of proteins that are causative of neurodegenerative disease. Inhibitors of PAR polymerase (PARP) activity have been developed as cancer therapeutics, raising the possibility that they could be used to treat neurodegenerative disease. We focus on pathways regulated by PAR in neurodegenerative disease, with emphasis on amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).
Topics: ADP-Ribosylation; Aging; Amyotrophic Lateral Sclerosis; Animals; Brain; Cells, Cultured; Drosophila; Frontotemporal Lobar Degeneration; Humans; Neurodegenerative Diseases; Neurons; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Protein Aggregation, Pathological; Protein Processing, Post-Translational
PubMed: 31182245
DOI: 10.1016/j.tig.2019.05.004 -
Life Science Alliance Jan 2023The modification of substrates with ADP-ribose (ADPr) is important in, for example, antiviral immunity and cancer. Recently, several reagents were developed to detect...
The modification of substrates with ADP-ribose (ADPr) is important in, for example, antiviral immunity and cancer. Recently, several reagents were developed to detect ADP-ribosylation; however, it is unknown whether they recognise ADPr, specific amino acid-ADPr linkages, or ADPr with the surrounding protein backbone. We first optimised methods to prepare extracts containing ADPr-proteins and observe that depending on the amino acid modified, the modification is heatlabile. We tested the reactivity of available reagents with diverse ADP-ribosylated protein and RNA substrates and observed that not all reagents are equally suited for all substrates. Next, we determined cross-reactivity with adenylylated RNA, AMPylated proteins, and metabolites, including NADH, which are detected by some reagents. Lastly, we analysed ADP-ribosylation using confocal microscopy, where depending on the fixation method, either mitochondrion, nucleus, or nucleolus is stained. This study allows future work dissecting the function of ADP-ribosylation in cells, both on protein and on RNA substrates, as we optimised sample preparation methods and have defined the reagents suitable for specific methods and substrates.
Topics: RNA; Indicators and Reagents; ADP-Ribosylation; Adenosine Diphosphate Ribose; Proteins; Amino Acids
PubMed: 36368907
DOI: 10.26508/lsa.202201455 -
DNA Repair Oct 2022ADP-ribosylation (ADPr) is a widespread post-translational modification (PTM) spanning all kingdoms of life. It is employed by bacteria and viruses in their war against... (Review)
Review
ADP-ribosylation (ADPr) is a widespread post-translational modification (PTM) spanning all kingdoms of life. It is employed by bacteria and viruses in their war against the host, and by eukaryotes to regulate many physiological processes, across almost all cellular compartments. PARP1, the founding member of the PARP family, is an early sensor of single- and double-strand breaks and catalyzes ADPr to mediate DNA damage repair. The recent discovery of Serine-ADPr and the PARP1 accessory factor HPF1 has brought a momentous change to the field. Bolstered by innovative ways to study ADPr, new and exciting research directions are rapidly emerging. In this review we explore our understanding of the HPF1/PARP1-mediated ADPr signaling pathway in DNA damage. We focus on the mechanistic steps leading to Serine-ADPr and its relevance in the DNA damage response. We discuss important technological advances that have enabled a nuanced study of Serine-ADPr, and conclude with an overview of the role of PARP inhibitors in cancer therapy.
Topics: ADP-Ribosylation; DNA Damage; DNA Repair; Poly (ADP-Ribose) Polymerase-1; Protein Processing, Post-Translational; Serine
PubMed: 35963141
DOI: 10.1016/j.dnarep.2022.103382 -
Nucleic Acids Research Jun 2019ADP-ribosylation is a reversible chemical modification catalysed by ADP-ribosyltransferases such as PARPs that utilize nicotinamide adenine dinucleotide (NAD+) as a...
ADP-ribosylation is a reversible chemical modification catalysed by ADP-ribosyltransferases such as PARPs that utilize nicotinamide adenine dinucleotide (NAD+) as a cofactor to transfer monomer or polymers of ADP-ribose nucleotide onto macromolecular targets such as proteins and DNA. ADP-ribosylation plays an important role in several biological processes such as DNA repair, transcription, chromatin remodelling, host-virus interactions, cellular stress response and many more. Using biochemical methods we identify RNA as a novel target of reversible mono-ADP-ribosylation. We demonstrate that the human PARPs - PARP10, PARP11 and PARP15 as well as a highly diverged PARP homologue TRPT1, ADP-ribosylate phosphorylated ends of RNA. We further reveal that ADP-ribosylation of RNA mediated by PARP10 and TRPT1 can be efficiently reversed by several cellular ADP-ribosylhydrolases (PARG, TARG1, MACROD1, MACROD2 and ARH3), as well as by MACROD-like hydrolases from VEEV and SARS viruses. Finally, we show that TRPT1 and MACROD homologues in bacteria possess activities equivalent to the human proteins. Our data suggest that RNA ADP-ribosylation may represent a widespread and physiologically relevant form of reversible ADP-ribosylation signalling.
Topics: ADP Ribose Transferases; ADP-Ribosylation; Adenosine Diphosphate; Adenosine Diphosphate Ribose; Animals; Catalysis; Chromatin; DNA Repair; DNA Repair Enzymes; DNA, Single-Stranded; Escherichia coli; Humans; Hydrolases; Mice; NAD; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Plasmids; Poly(ADP-ribose) Polymerases; Protein Processing, Post-Translational; Proto-Oncogene Proteins; RNA; Signal Transduction
PubMed: 31216043
DOI: 10.1093/nar/gkz305 -
Molecular Cell Jun 2021ARH3/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...
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.
Topics: ADP-Ribosylation; Adenosine Diphosphate Ribose; Cell Line, Tumor; Chromatin; DNA; DNA Damage; Fibroblasts; Glycoside Hydrolases; HEK293 Cells; HeLa Cells; Humans; Poly ADP Ribosylation; Poly Adenosine Diphosphate Ribose; Primary Cell Culture
PubMed: 34019811
DOI: 10.1016/j.molcel.2021.04.028 -
IScience May 2021While protein ADP-ribosylation was reported to regulate differentiation and dedifferentiation, it has so far not been studied during transdifferentiation. Here, we found...
While protein ADP-ribosylation was reported to regulate differentiation and dedifferentiation, it has so far not been studied during transdifferentiation. Here, we found that MyoD-induced transdifferentiation of fibroblasts to myoblasts promotes the expression of the ADP-ribosyltransferase . Comprehensive analysis of the genome architecture by Hi-C and RNA-seq analysis during transdifferentiation indicated that ARTD1 locally contributed to A/B compartmentalization and coregulated a subset of MyoD target genes that were however not sufficient to alter transdifferentiation. Surprisingly, the expression of ARTD1 was accompanied by the continuous synthesis of nuclear ADP ribosylation that was neither dependent on the cell cycle nor induced by DNA damage. Conversely to the HO-induced ADP-ribosylation, the MyoD-dependent ADP-ribosylation was not associated to chromatin but rather localized to the nucleoplasm. Together, these data describe a MyoD-induced nucleoplasmic ADP-ribosylation that is observed particularly during transdifferentiation and thus potentially expands the plethora of cellular processes associated with ADP-ribosylation.
PubMed: 33997706
DOI: 10.1016/j.isci.2021.102432 -
Biomolecules Mar 2022Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis.... (Review)
Review
Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules, regulating a multitude of key functional processes as diverse as DNA damage repair (DDR), transcriptional regulation, intracellular transport, immune and stress responses, and cell survival. Additionally, due to the emerging role of ADP-ribosylation in pathological processes, ADP-ribosyltransferases (ARTs), the enzymes involved in ADPr, are attracting growing interest as new drug targets. In this review, an overview of human ARTs and their related biological functions is provided, mainly focusing on the regulation of ADP-ribosyltransferase Diphtheria toxin-like enzymes (ARTD)-dependent RNA functions. Finally, in order to unravel novel gene functional relationships, we propose the analysis of an inventory of human gene clusters, including , which share conserved sequences at 3' untranslated regions (UTRs).
Topics: ADP Ribose Transferases; ADP-Ribosylation; Biology; Humans; Protein Processing, Post-Translational; RNA
PubMed: 35327636
DOI: 10.3390/biom12030443 -
Genes & Development Mar 2020ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its... (Review)
Review
ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its molecular functions and biological roles, as well as the activity of the ADP-ribose (ADPR) transferase enzymes (PARP family members) that catalyze it. Growing evidence indicates that PARP-mediated ADPRylation events are key regulators of the protein biosynthetic pathway, leading from rDNA transcription and ribosome biogenesis to mRNA synthesis, processing, and translation. In this review we describe the role of PARP proteins and ADPRylation in all facets of this pathway. PARP-1 and its enzymatic activity are key regulators of rDNA transcription, which is a critical step in ribosome biogenesis. An emerging role of PARPs in alternative splicing of mRNAs, as well as direct ADPRylation of mRNAs, highlight the role of PARP members in RNA processing. Furthermore, PARP activity, stimulated by cellular stresses, such as viral infections and ER stress, leads to the regulation of mRNA stability and protein synthesis through posttranscriptional mechanisms. Dysregulation of PARP activity in these processes can promote disease states. Collectively, these results highlight the importance of PARP family members and ADPRylation in gene regulation, mRNA processing, and protein abundance. Future studies in these areas will yield new insights into the fundamental mechanisms and a broader utility for PARP-targeted therapeutic agents.
Topics: ADP-Ribosylation; Animals; Gene Expression; Humans; Poly(ADP-ribose) Polymerases; Protein Biosynthesis; Protein Processing, Post-Translational; Proteostasis; RNA
PubMed: 32029452
DOI: 10.1101/gad.334433.119