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]
Summary
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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