An auto-generated ADP-ribosyl-cysteine degron drives DTX2-dependent turnover of PARP7

YANG, C.; Wierbilowicz, K.; Jang, H.; Wu, J. S.; Buch-Larsen, S. C.; Diefenderfer, G. R.; Genetta, T. L.; Olsen, J. V.; Larner, J. M.; Nielsen, M. L.; Ratan, A.; Paschal, B. M.

doi:10.64898/2026.10.26.761924

bioRxiv · 10.64898/2026.10.26.761924

An auto-generated ADP-ribosyl-cysteine degron drives DTX2-dependent turnover of PARP7

YANG, C.·Wierbilowicz, K.·Jang, H.·Wu, J. S.·Buch-Larsen, S. C.·Diefenderfer, G. R.·Genetta, T. L.·Olsen, J. V.·Larner, J. M.·Nielsen, M. L.·Ratan, A.·Paschal, B. M.

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Abstract

The mono-ADP-ribosyltransferase PARP7 exerts negative feedback on androgen receptor (AR) signaling by generating an ADP-ribosyl-cysteine degron on AR that marks it for degradation. Here we show that the protein half-life of PARP7 is set by cysteine auto-ADP-ribosylation, providing a mechanism for temporal control of its feedback on AR-dependent transcription in prostate cancer cells. ADP-ribosyl-cysteine in the PARP7 catalytic domain constitutes a degron read by the E3 ligase DTX2, driving PARP7 polyubiquitination and proteasomal degradation. Thus, the same E3 is used to degrade both PARP7 and its substrate AR. Using label-free mass spectrometry, we identify the AP-1 factor c-JUN as a PARP7 substrate and show that ADP-ribosylated c-JUN accumulates upon DTX2 depletion. ADP-ribosyl degron formation is dependent on NAD+ availability since depleting NAD+ pharmacologically or under hypoxia prevents degron formation and stabilizes PARP7 in a catalytically constrained state that compromises its feedback activity. Correlations between PARP7 expression and hypoxia signatures in prostate tumors, together with sensitivity to the PARP7-selective inhibitor RBN-2397 across cancer lines, nominate hypoxic, NAD+ depleted contexts as heightened vulnerability to PARP7-targeting agents. Marking transcription factors for degradation by covalent ADP-ribosylation is emerging as a distinct mode of transcriptional control.

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YANG, C., Wierbilowicz, K., Jang, H., Wu, J. S., Buch-Larsen, S. C., Diefenderfer, G. R., Genetta, T. L., Olsen, J. V., Larner, J. M., Nielsen, M. L., Ratan, A., Paschal, B. M.. 2026-10-28. An auto-generated ADP-ribosyl-cysteine degron drives DTX2-dependent turnover of PARP7. https://doi.org/10.64898/2026.10.26.761924

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