Abstract

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.

Highlights

  • Adenosine diphosphate (ADP)-ribosylation is a covalent modification in which the ADP-ribose (ADPr) group from nicotinamide adenine dinucleotide (NAD+) is transferred to diverse target molecules: proteins, nucleic acids and small molecules such as phosphate or acetate [1]

  • We analysed RNA ADP-ribosylation catalysed by PARP10 catalytic domain in the excess presence of adenosine mono-phosphate (AMP) or 5 -phosphoadenosine 3 phosphate (PAP) as potential competitors and we observed no significant change in RNA modification in presence of nucleotide analogue in excess (Supplementary Figure S1D)

  • For the first time, that ADPribosylation of RNA can be catalysed by a few members of Poly(ADP-ribose) polymerases (PARPs) family––PARP10, PARP11, PARP15 and a PARPlike protein –TRPT1 previously characterized as an NAD+ dependent phosphotransferase [50,51]

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Summary

Introduction

Adenosine diphosphate (ADP)-ribosylation is a covalent modification in which the ADP-ribose (ADPr) group from nicotinamide adenine dinucleotide (NAD+) is transferred to diverse target molecules: proteins, nucleic acids and small molecules such as phosphate or acetate [1]. This modification changes physical and chemical properties or localization of target molecules and regulates many important cellular processes in both prokaryotes and eukaryotes [2]. Poly(ADP-ribose) polymerases (PARPs), the best studied and largest ART subgroup, belong to diphtheria toxin-like ADP-ribosyl transferases. Several PARP family members (PARP1, PARP2 and tankyrases) synthesize long chains of poly-ADPr, while the other PARP family members transfer a single ADPr group on targets (such as PARP3 and PARP16) [7]

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