Serine is the major residue for ADP-ribosylation upon DNA damage

Palazzo, Luca; Leidecker, Orsolya; Prokhorova, Evgeniia; Dauben, Helen; Matić, Ivan; Ahel, Ivan

doi:10.7554/elife.34334

Cited by 199 publications

(245 citation statements)

References 34 publications

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“…ADP-ribosylation is a dynamic chemical modification that is regulated both at the level of addition and the removal of ADPr groups. PARPs have been shown to target mostly Glu/Asp or Ser residues (8)(9)(10)(11)(12). Poly-ADP-ribosylation can be removed by the action of two divergent enzymes, poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3) (13,14).…”

Section: Introductionmentioning

confidence: 99%

Reversible ADP-ribosylation of RNA

Munnur

Bartlett

Mikolčević

et al. 2019

Nucleic Acids Research

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129

189

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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.

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Section: Introductionmentioning

confidence: 99%

Reversible ADP-ribosylation of RNA

Munnur

Bartlett

Mikolčević

et al. 2019

Nucleic Acids Research

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129

189

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“…This activity has been observed in human cancer cells (515,516). Serine ADP-ribosylation is a widespread and important PTM, appearing after DNA damage on histones (225,517,518) and high-mobility group proteins, DNA repair factors, and other proteins (519,520). The sequence motifs KS and RS were shown to identify substrate proteins (516).…”

Section: Marylation and Its Reversalmentioning

confidence: 90%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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“…Conversely, eukaryotic ARTD/ PARP group modifies a multitude of proteins targeting several amino acid residues through a selective mechanism that is still unknown. Amino acids modified by eukaryotic ARTD include serine (abbreviated as Ser-ADPr) and tyrosine (Tyr-ADPr) through O-glycosylation bonds [115,[143][144][145][146][147], negatively charged residues such as glutamic and aspartic amino acids through ester linkages [148,149], positively charged lysine through N-glycosidic bond [150], glycine as in the case of PARP9 [108] and cysteine as reported for PARP8 [43].…”

Section: Amino Acids Modified By Adprmentioning

confidence: 99%

“…Strikingly, modified residues within protein substrates appear spatially restricted within cellular sub-compartments, for instance Tyr-ADPr enriches at ribosomal proteins with the most significant motif consisting of a lysine residue at the +1 position of the modified tyrosine; Arg-ADPr enriches at the ER primarily onto RNA binding proteins, with the motif flanking the arginine residue enriched with serine, and histidine-ADPr enriches at the mitochondrion [151]. Importantly, residues modified by ADPr are also target of additional post-translational modifications (PTMs), such as of phosphorylation, thus suggesting an essential role for ADPr in cross-regulating PTMs in a timedependent fashion [144,145,147,151].…”

Section: Amino Acids Modified By Adprmentioning

confidence: 99%

“…A well-studied example of specificity for modification sites within protein substrates induced by interacting proteins has been shown for PARP1. The interaction of PARP1 with histone PARylation factor 1 (HPF1) induces PARP1-dependent in trans modification of histones and other DNA repair factors onto serine residues, thus limiting the ability of PARP1 to automodify onto acidic residues [76,144,152].…”

Section: Amino Acids Modified By Adprmentioning

confidence: 99%

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Targeting ADP-ribosylation as an antimicrobial strategy

Catara

Corteggio

Valente

et al. 2019

Biochemical Pharmacology

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A B S T R A C T ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.T large number of worldwide spread diseases, affecting humans, insects and plants [31,[56][57][58], with a great impact on human health. In addition, infectious diseases strongly affect the world economy in terms of costs for the human health as well as food and agricultural economic losses [59]. The use of antibiotics to counteract the pathogen infections has represented the therapeutic strategy of choice in the last century, however the emergence of antibiotic resistance strains represents the major challenge of the 21st century [60][61][62]. Targeting bacterial pathogenic mechanisms by disarming pathogens of virulence factors, for instance by inhibiting the enzymatic activity of bART, represents a valid alternative intervention strategy to overcome antibiotic resistance [63][64][65][66]. In addition, because of the conservation of ADPr systems throughout the evolution, the understanding of bacterial pathogenic mechanisms may contribute to unveil novel and conserved cellular processes regulated by ADPr in high organisms [34,45,67,68]. The dysregulation of such processes can be either cause of human diseases or be target of therapeutic intervention [39,[69][70][71].Herein, we will provide a summary of bacterial ADPr systems describing their pathogenic mechanisms and highlighting the similarities with ADPr systems in mammals as well. Further, we discuss the potential of targeting ADPr for therapeutic strategies of infection diseases. ADP-ribosylation in pathophysiologyADPr was originally described in the 60s; two independent studies reported the identification of a new polymer, poly(ADP-ribose) (PAR) synthesised from NAD + in vertebrate cells [72] and, simultaneously, the finding that bacterial DTX activity from C. diphteriae is dependent on NAD + content [73]. In the following decades, research in the field has expanded the involvement of ADPr ...

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Serine is the major residue for ADP-ribosylation upon DNA damage

Cited by 199 publications

References 34 publications

Reversible ADP-ribosylation of RNA

Reversible ADP-ribosylation of RNA

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Targeting ADP-ribosylation as an antimicrobial strategy

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