Avoid the trap: Targeting PARP1 beyond human malignancy

PARP1 is a poly(ADP-ribose) polymerase (PARP) enzyme that plays a critical role in regulating DNA damage response. The main enzymatic function of PARP1 is to catalyze a protein post-translational modification known as poly(ADP-ribosyl)ation (PARylation). Human cancers with homologous recombination deficiency are highly sensitive to PARP1 inhibitors. PARP1 is aberrantly activated in many non-oncological diseases, leading to the excessive NAD(+) depletion and PAR formation, thus causing cell death and tissue damage. PARP1 deletion offers a profound protective effect in the relevant animal models. However, many of the current PARP1 inhibitors also induce PARP1 trapping, which drives subsequent DNA damage, innate immune response and cytotoxicity. This minireview provides an overview of the basic biology of PARP1 trapping, and its implications in disease. Furthermore, we also discuss the recent development of PARP1 PROTAC compounds, and their utility as non-trapping'' PARP1 degraders for the potential amelioration of non-oncological diseases driven by aberrant PARP1 activation.

Automated summary

PARP1 plays a critical role in regulating DNA damage response and is sensitive to PARP1 inhibitors in cancers with homologous recombination deficiency. Aberrant activation of PARP1 in non-oncological diseases can lead to cell death, and while PARP1 deletion offers protection in animal models, current PARP1 inhibitors may induce PARP1 trapping, causing DNA damage and cytotoxicity. Research on PARP1 PROTAC compounds for potential use in non-oncological diseases is ongoing.