PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities

Đukic, N.; Stromland, O.; Munnur, D.; Zhu, K.; Schuller, M.; Chatrin, C.; Kar, P.; Rack, J. G. M.; Baretic, D.; Schüler, H.; Wijngaarden, S.; Filippov, D. V.; Sanyal, S.; Smith, R.; Ahel, D.; Ahel, I.

doi:10.1101/2023.06.25.546318

bioRxiv · 10.1101/2023.06.25.546318

PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities

Đukic, N.·Stromland, O.·Munnur, D.·Zhu, K.·Schuller, M.·Chatrin, C.·Kar, P.·Rack, J. G. M.·Baretic, D.·Schüler, H.·Wijngaarden, S.·Filippov, D. V.·Sanyal, S.·Smith, R.·Ahel, D.·Ahel, I.

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Abstract

PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription and DNA replication stress management. However, little is known about the ADP-ribosylation activity of PARP14, including its substrate specificity or how PARP14-dependent ADP-ribosylation is reversed. Here we show that PARP14 is dual function enzyme with both ADP-ribosyl transferase and hydrolase activity acting on both protein and nucleic acid substrates. In particular, we show that the PARP14 macrodomain 1 is an active ADP-ribosyl hydrolase. We also demonstrate hydrolytic activity for the first macrodomain of PARP9. We reveal that expression of a PARP14 mutant with the inactivated macrodomain 1 results in a dramatic increase in mono(ADP-ribosyl)ation of proteins in human cells, including PARP14 itself and antiviral PARP13. Moreover, we demonstrate that the closely related hydrolytically active macrodomain of SARS2 Nsp3, Mac1, efficiently reverses PARP14 ADP-ribosylation in vitro and in cells, supporting the evolution of viral macrodomains to counteract PARP14-mediated antiviral response. TeaserPARP14 is an antiviral PARP that combines ADP-ribosylation writer, reader and eraser functions in one polypeptide.

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Đukic, N., Stromland, O., Munnur, D., Zhu, K., Schuller, M., Chatrin, C., Kar, P., Rack, J. G. M., Baretic, D., Schüler, H., Wijngaarden, S., Filippov, D. V., Sanyal, S., Smith, R., Ahel, D., Ahel, I.. 2023-06-26. PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities. https://doi.org/10.1101/2023.06.25.546318

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