Nature cell biologyJun 2, 2026

Cell cleanup process removes harmful trapped PARP1 protein

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 3, 2026

Abstract

Trapped PARP1 is cleared via nucleophagy, a process linked to cancer cell sensitivity to PARP inhibitors.

In homologous recombination repair-deficient cancers, PARP inhibitors induce DNA damage by trapping PARP1 on chromatin.
Increased clearance of trapped PARP1 may reduce cancer cell sensitivity to PARP inhibitors.
PARP inhibitor exposure is associated with enhanced autophagy flux, while inhibiting autophagy may increase sensitivity to PARP inhibitors.
The selective autophagy receptor TEX264 and the segregase p97 are involved in the degradation of trapped PARP1.
Disruption of the nucleophagy pathway can lead to increased PARP1 trapping, resulting in protein aggregates and cell death.
Nucleophagy may play a protective role by targeting trapped PARP1 for degradation, thus influencing cancer cell response to PARP inhibitors.

Simplified

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HR)-deficient (HRD) cancers by trapping PARP1 on chromatin, thereby causing irreparable replication-associated DNA damage. Although increased clearance of trapped PARP1 from chromatin reduces the sensitivity of cancer cells to PARPi, details surrounding this process remain unclear. PARPi exposure is known to cause increased autophagy flux, whereas autophagy inhibition can hypersensitize cells to PARPi. Our study reveals that trapped PARP1 is cleared via nucleophagy, with the selective autophagy receptor TEX264 and its partner segregase p97 (also known as VCP) orchestrating this process. TEX264 interacts directly with trapped PARP1, linking it to the autophagosomal protein LC3 for degradation. Disrupting this pathway, either chemically or genetically, increases PARP1 trapping, resulting in protein aggregates, DNA damage and cell lethality, ultimately re-sensitizing PARPi-resistant cells. We conclude that nucleophagy serves a cytoprotective role by targeting PARPi-induced trapped PARP1 for degradation.

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Funding

Competing interests

Competing interests: C.J.L. receives and/or has received research funding from AstraZeneca, Merck KGaA, Artios, Neophore and FoRx; received consultancy, scientific advisory board membership or honoraria payments from FoRx, Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango Therapeutics, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, Neophore, Glaxo Smith Kline, Dawn Bioventures, Blacksmith Medicines, ForEx and Ariceum; and has stock in Tango, Ovibio, Hysplex, Tesselate and Ariceum. C.J.L. is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR ‘Rewards to Inventors’ scheme, and also reports benefits from this scheme associated with patents for PARP inhibitors paid into C.J.L.’s personal account and research accounts at the Institute of Cancer Research. All other authors declare no competing interests.

PubMed

Cell cleanup process removes harmful trapped PARP1 protein

Abstract

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Funding

Competing interests

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