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Review
. 2022 Mar 13;12(3):443.
doi: 10.3390/biom12030443.

ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives

Giuseppe Manco  1 , Giuseppina Lacerra  2 , Elena Porzio  1 , Giuliana Catara  1
Affiliations
Review

ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives

Giuseppe Manco et al. Biomolecules. .

Abstract

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 ARTDs, which share conserved sequences at 3' untranslated regions (UTRs).

Keywords: ADP-ribosylation; ARTs; MARylation; PARylation; mRNA regulation; poly-ADP-ribosylpolymerases (PARPs).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the ADP-ribosylation reaction onto acceptor protein. (a) Mono-ADP-ribosylation reaction is catalyzed by human ARTDs in the presence of the NAD+. Inset 1. The modification is reversed by selective ADP-ribosylhydrolases (MacroD1, MacroD2, TARG1, ARH1, ARH3) that display different amino acid–ADP-ribose linkage specificity, and by phosphodiesterases (NUDT16 and ENPP1). (b) Poly-ADP-ribosylation reaction is catalyzed by human ARTDs. Inset 2. Linear or branched chains of poly-ADP-ribose are hydrolyzed by selective ADP-riboshydrolases (PARG, ARH3, TARG1) and by phosphodiesterases (NUDT16 and ENPP1). Further details are reported in the text. ARH1/ARH3, ADP-ribosyl acceptor hydrolases 1/3; NUDT16, nudix hydroxylase 16; PARG, poly-ADP-ribosyl glycohydrolase (endo-glyc, endo-glycolytic activity; exo-glyc, exo-glycolitic activity); TARG1, Terminal ADP-ribose glycosylhydrolase 1.
Figure 2
Figure 2
Representation of the GO analysis using the 21 genes list of Cluster 2 as input (Table S1 [194, 197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218]): (a) categorization by protein class; (b) grouping by molecular functions. Six genes, namely PARP12, DICER1, LUZP4, UPF3B, ZFAND3, and OSGIN2, are not included.
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