Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack
Nucleic acid ADP-ribosylation and its associated enzymes involved in catalysis and hydrolysis are widespread among all kingdoms of life. Yet, its roles in mammalian and bacterial physiology including inter-/intraspecies conflicts are currently underexplored. Recently, several examples of enzymatic s...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2025
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| _version_ | 1824459357824221184 |
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| author | Lu, Y Schuller, M Bullen, N Mikolcevic, P Zonjic, I Raggiaschi, R Mikoc, A Whitney, J Ahel, I |
| author_facet | Lu, Y Schuller, M Bullen, N Mikolcevic, P Zonjic, I Raggiaschi, R Mikoc, A Whitney, J Ahel, I |
| author_sort | Lu, Y |
| collection | OXFORD |
| description | Nucleic acid ADP-ribosylation and its associated enzymes involved in catalysis and hydrolysis are widespread among all kingdoms of life. Yet, its roles in mammalian and bacterial physiology including inter-/intraspecies conflicts are currently underexplored. Recently, several examples of enzymatic systems for RNA ADP-ribosylation have been identified, showing that all major types of RNA species, including messenger RNA, ribosomal RNA, and transfer RNA, can be targeted by ADP-ribosyltransferases (ARTs) which attach ADP-ribose modifications either to nucleobases, the backbone ribose, or phosphate ends. Yet little is known about the reversibility of RNA ADP-ribosylation by ADP-ribosylhydrolases belonging to the macrodomain, ARH, or NADAR superfamilies. Here, we characterize the hydrolytic activity of ADP-ribosylhydrolases on RNA species ADP-ribosylated by mammalian and bacterial ARTs. We demonstrate that NADAR ADP-ribosylhydrolases are the only hydrolase family able to reverse guanosine RNA base ADP-ribosylation while they are inactive on phosphate-end RNA ADP-ribosylation. Furthermore, we reveal that macrodomain-containing PARG enzymes are the only hydrolase type with the ability for specific and efficient reversal of 2′-hydroxyl group RNA ADP-ribosylation catalysed by Pseudomonas aeruginosa effector toxin RhsP2. Moreover, using the RhsP2/bacterial PARG system as an example, we demonstrate that PARG enzymes can act as protective immunity enzymes against antibacterial RNA-targeting ART toxins. |
| first_indexed | 2025-02-19T04:40:30Z |
| format | Journal article |
| id | oxford-uuid:aca40269-c832-4f90-91e5-eec9f25de95f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:40:30Z |
| publishDate | 2025 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:aca40269-c832-4f90-91e5-eec9f25de95f2025-02-18T20:19:24ZDiscovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attackJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:aca40269-c832-4f90-91e5-eec9f25de95fEnglishJisc Publications RouterOxford University Press2025Lu, YSchuller, MBullen, NMikolcevic, PZonjic, IRaggiaschi, RMikoc, AWhitney, JAhel, INucleic acid ADP-ribosylation and its associated enzymes involved in catalysis and hydrolysis are widespread among all kingdoms of life. Yet, its roles in mammalian and bacterial physiology including inter-/intraspecies conflicts are currently underexplored. Recently, several examples of enzymatic systems for RNA ADP-ribosylation have been identified, showing that all major types of RNA species, including messenger RNA, ribosomal RNA, and transfer RNA, can be targeted by ADP-ribosyltransferases (ARTs) which attach ADP-ribose modifications either to nucleobases, the backbone ribose, or phosphate ends. Yet little is known about the reversibility of RNA ADP-ribosylation by ADP-ribosylhydrolases belonging to the macrodomain, ARH, or NADAR superfamilies. Here, we characterize the hydrolytic activity of ADP-ribosylhydrolases on RNA species ADP-ribosylated by mammalian and bacterial ARTs. We demonstrate that NADAR ADP-ribosylhydrolases are the only hydrolase family able to reverse guanosine RNA base ADP-ribosylation while they are inactive on phosphate-end RNA ADP-ribosylation. Furthermore, we reveal that macrodomain-containing PARG enzymes are the only hydrolase type with the ability for specific and efficient reversal of 2′-hydroxyl group RNA ADP-ribosylation catalysed by Pseudomonas aeruginosa effector toxin RhsP2. Moreover, using the RhsP2/bacterial PARG system as an example, we demonstrate that PARG enzymes can act as protective immunity enzymes against antibacterial RNA-targeting ART toxins. |
| spellingShingle | Lu, Y Schuller, M Bullen, N Mikolcevic, P Zonjic, I Raggiaschi, R Mikoc, A Whitney, J Ahel, I Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack |
| title | Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack |
| title_full | Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack |
| title_fullStr | Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack |
| title_full_unstemmed | Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack |
| title_short | Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack |
| title_sort | discovery of reversing enzymes for rna adp ribosylation reveals a possible defence module against toxic attack |
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