Reversible RNA ADP-ribosylation on uracil bases

Mar 31, 2026Nucleic acids research

Reversible RNA modification involving ADP-ribose added to uracil bases

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Abstract

Human PARP10 is identified as an enzyme that ADP-ribosylates nucleic acid bases, specifically uracil in RNA and thymine in DNA.

ADP-ribosylation is a process that modifies nucleic acids, with implications for cellular functions like genome stability.
Human PARP10 shows significant activity on uracil bases in RNA, while its activity on thymine bases in DNA is weaker.
Human TARG1, linked to neurodegenerative disorders, reverses uracil base ADP-ribosylation efficiently.
Chemical probes were developed to better characterize the enzymes responsible for reversing uracil base ADP-ribosylation.
TARG1 and similar proteins are identified as effective hydrolases for uracil base ADP-ribosylation reversal across humans, fruit flies, and bacteria.
The presence of uracil ADP-ribosylation hydrolases in diverse organisms suggests a potential evolutionary conservation of this modification.

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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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Reversible RNA ADP-ribosylation on uracil bases

Abstract

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