Human PARPs modify RNA nucleobases in vitro and in cells

作者：Michael U. Musheev, Jonas Siefert, Wiwik Bauten, Mareike Bütepage, Bernhard Luscher, Christof Niehrs, Karla L. H. Feijs-Žaja, Roko Žaja · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.03.31.715305 · 研究领域：PARP inhibition in cancer therapy、RNA modifications and cancer、RNA Research and Splicing

SUMMARY 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.