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Selective nucleophagy removes cytotoxic trapped PARP1

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277366 | GEO | 2026/03/23

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE277366_C_KO_TalavsC_WT_Tala_deg.xls.gz	Xls
	GSE277366_C_WT_TalavsC_WT_utd_deg.xls.gz	Xls
	GSE277366_H_KO_TalavsH_WT_Tala_deg.xls.gz	Xls
	GSE277366_H_WT_TalavsH_WT_utd_deg.xls.gz	Xls

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Project description:Prostate cancer (PCa) is the second most lethal cancer in men in the United States. African American (AA) men have twice the incidence and death rate from the disease than European American (EA) men. Early-stage PCa is treated with hormone deprivation therapy, although patients frequently experience relapse. Advanced stage PCa is associated with increased expression and activity of the DNA damage/repair pathway enzyme, poly (ADP-ribose) polymerase 1 (PARP1). Furthermore, PARP1 inhibitors are FDA-approved for the treatment of advanced PCa tumors that carry mutations in components of a specific DNA damage/repair pathway termed homologous recombination repair (HRR). However, PARPi also provide benefit in model systems without HRR incompetencies. A number of different PARPi have now been developed, tested and approved for use in PCa. These inhibitors utilize multiple biochemical mechanisms of action and exhibit distinct potencies and toxicity profiles. While there is emerging evidence of differences in DNA damage/repair pathway enzyme expression between EA and AA men, PARP1 itself has not been fully explored in the context of race. This study hypothesized that 1) AA and EA PCa may respond differently to PARPi and 2) different PARPi may differentially impact the transcriptome, irrespective of HRR status. To test these hypotheses, PCa patient samples from a racially diverse cohort were examined to define race-based differences in PARP activity/expression. Additionally, biologically relevant doses of five clinically relevant PARPi were established across multiple PCa lines carrying different genetic backgrounds, HRR status, and hormone therapy sensitivities. Collectively, these findings demonstrate a link between racial background and PARP1 expression/activity and define a core transcriptional response that lies downstream of all five PARPi, while simultaneously defining transcriptional programs unique to each inhibitor. These findings broaden our understanding of the effector pathways downstream of individual PARPi and provide a compelling rationale for a broader exploration of the impact of race on the response to PARPi. They may also help refine personalized recommendations for use of specific PARPi.

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Selective nucleophagy removes cytotoxic trapped PARP1

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