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Reversible RNA ADP-ribosylation on uracil bases

Lu, Yang ; Tang, Li ; Strømland, Øyvind ; Chatrin, Chatrin ; Zhu, Kang ; Munnur, Deeksha ; Groslambert, Joséphine ; Mikolčević, Petra ; Schüler, Herwig LU orcid and Timinszky, Gyula , et al. (2026) In Nucleic Acids Research 54(6).
Abstract

ADP-ribosylation is a conserved modification that uses NAD+ as a co-substrate to regulate essential cellular processes, such as genome stability and transcription, with Poly(ADP-ribose) Polymerases (PARPs) serving as the major catalyzing enzymes in humans. Historically defined as a protein post-translational modification, ADP-ribosylation on nucleic acids has been increasingly recognized in recent years, particularly in bacterial systems, but remains poorly understood in higher organisms. Here, we identify human PARP10 as a candidate enzyme that ADP-ribosylates nucleic acid bases, showing apparent activity on uracil bases in RNA, and a relatively weaker activity toward thymine bases in DNA. Furthermore, we show that human... (More)

ADP-ribosylation is a conserved modification that uses NAD+ as a co-substrate to regulate essential cellular processes, such as genome stability and transcription, with Poly(ADP-ribose) Polymerases (PARPs) serving as the major catalyzing enzymes in humans. Historically defined as a protein post-translational modification, ADP-ribosylation on nucleic acids has been increasingly recognized in recent years, particularly in bacterial systems, but remains poorly understood in higher organisms. Here, we identify human PARP10 as a candidate enzyme that ADP-ribosylates nucleic acid bases, showing apparent activity on uracil bases in RNA, and a relatively weaker activity toward thymine bases in DNA. Furthermore, we show that human TARG1, a neurodegenerative disorder-linked protein previously reported to hydrolyse thymine base ADP-ribosylation, also efficiently reverses uracil base ADP-ribosylation (U-ADPr). To improve the efficient characterization of the enzymes for U-ADPr reversal, we developed chemical probes. Using these probes, we demonstrated that human TARG1 and TARG1-like macrodomain proteins are the efficient hydrolases for U-ADPr reversal in humans, Drosophila melanogaster, and bacterial homologues. The widespread distribution of U-ADPr hydrolases among different organisms suggests the potential evolutionary conservation of U-ADPr as a biological signal.

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type
Contribution to journal
publication status
published
subject
in
Nucleic Acids Research
volume
54
issue
6
publisher
Oxford University Press
external identifiers
  • pmid:41914495
  • scopus:105034704421
ISSN
0305-1048
DOI
10.1093/nar/gkag289
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2026. Published by Oxford University Press.
id
34c1927d-5618-40ce-9108-cc65694913f1
date added to LUP
2026-05-27 13:09:48
date last changed
2026-10-02 18:37:15
@article{34c1927d-5618-40ce-9108-cc65694913f1,
  abstract     = {{<p>ADP-ribosylation is a conserved modification that uses NAD<sup>+</sup> as a co-substrate to regulate essential cellular processes, such as genome stability and transcription, with Poly(ADP-ribose) Polymerases (PARPs) serving as the major catalyzing enzymes in humans. Historically defined as a protein post-translational modification, ADP-ribosylation on nucleic acids has been increasingly recognized in recent years, particularly in bacterial systems, but remains poorly understood in higher organisms. Here, we identify human PARP10 as a candidate enzyme that ADP-ribosylates nucleic acid bases, showing apparent activity on uracil bases in RNA, and a relatively weaker activity toward thymine bases in DNA. Furthermore, we show that human TARG1, a neurodegenerative disorder-linked protein previously reported to hydrolyse thymine base ADP-ribosylation, also efficiently reverses uracil base ADP-ribosylation (U-ADPr). To improve the efficient characterization of the enzymes for U-ADPr reversal, we developed chemical probes. Using these probes, we demonstrated that human TARG1 and TARG1-like macrodomain proteins are the efficient hydrolases for U-ADPr reversal in humans, Drosophila melanogaster, and bacterial homologues. The widespread distribution of U-ADPr hydrolases among different organisms suggests the potential evolutionary conservation of U-ADPr as a biological signal.</p>}},
  author       = {{Lu, Yang and Tang, Li and Strømland, Øyvind and Chatrin, Chatrin and Zhu, Kang and Munnur, Deeksha and Groslambert, Joséphine and Mikolčević, Petra and Schüler, Herwig and Timinszky, Gyula and Gabant, Guillaume and Suskiewicz, Marcin J. and Mikoč, Andreja and Aucagne, Vincent and Ahel, Dragana and Liu, Qiang and Ahel, Ivan}},
  issn         = {{0305-1048}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{6}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{Reversible RNA ADP-ribosylation on uracil bases}},
  url          = {{http://dx.doi.org/10.1093/nar/gkag289}},
  doi          = {{10.1093/nar/gkag289}},
  volume       = {{54}},
  year         = {{2026}},
}