PARP1 hyperactivation uncouples transcription from protein expression through nuclear RNA retention

The DNA damage response triggers widespread transcriptional changes and modulates protein degradation, yet its role in regulating translation remains largely unexplored. Here, we uncover that hyperactivated PARP1 suppresses global mRNA translation by inducing nuclear RNA retention. Mechanistically, we find that APE1-dependent cleavage of abasic sites drives PARP1 hyperactivation, leading to translation arrest in human cells. Elevated PAR synthesis by PARP1 directly competes with RNA for binding to multiple RNA-binding proteins, disrupting RNA splicing and export and promoting the formation of PARP1-dependent nuclear condensates. As a result, RNA accumulates in the nucleus, reducing the amount of cytoplasmic mRNA available for translation. Moreover, we show that PARP1 hyperactivation inhibits the expression of many DNA damage-induced stress response factors by blocking nuclear export of their mRNAs. Together, these findings reveal an unrecognized role for PARP1 as a post-transcriptional regulator of the DNA damage response, uncoupling gene transcription from translation into proteins.