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

PARP7 turnover in prostate cancer cells is driven by cysteine auto-ADP-ribosylation that forms an ADP-ribosyl-cysteine degron read by DTX2.

• Why it matters: Temporal control of PARP7’s negative feedback on androgen receptor (AR) signaling is needed, but how PARP7 is selectively degraded and regulated under metabolic stress was unclear.
• What they did: The study used label-free mass spectrometry to show ADP-ribosylated PARP7 catalytic-domain degrons are recognized by DTX2, promoting PARP7 polyubiquitination and proteasomal degradation. It also identified c-JUN as a PARP7 substrate and tested NAD+ depletion and hypoxia effects on degron formation.
• The result: Depleting NAD+ pharmacologically or under hypoxia prevents degron formation and stabilizes catalytically constrained PARP7, while DTX2 depletion causes ADP-ribosylated c-JUN to accumulate. Tumor correlations with hypoxia signatures and sensitivity to the PARP7-selective inhibitor RBN-2397 across cancer lines suggest hypoxic, NAD+-depleted contexts are heightened vulnerability to PARP7-targeting agents.