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bioRxiv · 10.64898/2026.03.31.715305

Human PARPs modify RNA nucleobases in vitro and in cells

Musheev, M. U.·Siefert, J.·Bauten, W.·Butepage, M.·Luscher, B.·Niehrs, C.·Feijs, K. L.·Zaja, R.
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Abstract

ADP-ribosylation is known as a protein modification, yet recent studies have expanded the range of ADP-ribosyltransferase (ART) substrates to include nucleic acids. tRNA 2'-phosphotransferase 1 (TRPT1) and several PARP family members can modify the 5'-phosphate of single-stranded RNA. Here, we show that PARP10 and PARP15 extend this activity beyond the 5'-phosphate terminus and generate N3-ADP-ribosyl uracil and N1-ADP-ribosyl guanine bases. The base-linked ADP-ribosylation is reversed selectively by the macrodomain-containing hydrolase TARG1. In TARG1 knockout cells, N1-ADP-ribosyl guanine can be detected. Together, these findings establish guanine and uracil ADP-ribose as two novel nucleotide modifications and reveal PARP15 and TARG1 as an enzyme pair which can dynamically regulate guanine ADP-ribosylation in living cells.

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Musheev, M. U., Siefert, J., Bauten, W., Butepage, M., Luscher, B., Niehrs, C., Feijs, K. L., Zaja, R.. 2026-03-31. Human PARPs modify RNA nucleobases in vitro and in cells. https://doi.org/10.64898/2026.03.31.715305

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