Selective nucleophagy removes cytotoxic trapped PARP1

Poly (ADP-ribose) polymerase inhibitors (PARPi) induce cytotoxicity in homologous recombination deficient cancers by causing PARP1 to become trapped on chromatin, resulting in irreparable replication-associated DNA damage. Cancer cells commonly develop resistance to PARPi, with a recently proposed mechanism being the clearance of trapped PARP1 from chromatin, yet details surrounding this process remain unclear. PARPi treatment causes increased autophagy flux, whilst autophagy inhibition can hypersensitise cells to PARPi. With selective autophagy of nuclear substrates (nucleophagy) shown, we wanted to explore if this occurs during DNA damage repair by clearance of trapped PARP1. We used various biochemical, cell biological and live imaging-based assays, demonstrating that trapped PARP1 is processed by selective nucleophagy. We identified that nucleophagy of trapped PARP1 is orchestrated by selective autophagy receptor TEX264 and its partner protein p97/VCP. TEX264 directly interacts with trapped PARP1, then bridges PARP1 to autophagosomal resident protein LC3 for processing via autophagy. Impeding this process, either chemically or genetically, heightened PARP1 trapping, leading to replication-associated DNA damage and cell lethality, re-sensitising PARPi-resistant cells to various PARPi. In conclusion, we show that selective nucleophagy acts in a cytoprotective manner to directly target PARPi-induced trapped PARP1 for degradation.