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Nucleophagy removes cytotoxic trapped PARP1
Gwendoline Hoslett1, Sara Tribble1, Pauline Lascaux1
1The MRC Weatherall Institute of Molecular Medicine, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Nature Cell Biology
|June 2, 2026
Summary
Poly(ADP-ribose) polymerase inhibitors trap PARP1 in cancer cells. Nucleophagy, mediated by TEX264 and p97, clears trapped PARP1, protecting cells from DNA damage and promoting survival.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective against homologous recombination repair-deficient (HRD) cancers by trapping PARP1 on chromatin, leading to DNA damage.
- The clearance mechanisms for PARP1 trapped on chromatin are not fully understood, yet are known to influence cancer cell sensitivity to PARPi.
- Autophagy flux increases upon PARPi exposure, and its inhibition can sensitize cells to PARPi, suggesting a role for autophagy in PARPi response.
Purpose of the Study:
- To elucidate the mechanism by which trapped PARP1 is cleared from chromatin.
- To identify the specific autophagy pathway and key proteins involved in the degradation of PARPi-induced trapped PARP1.
- To investigate the therapeutic potential of modulating this clearance pathway in PARPi-resistant cancers.
Main Methods:
- Utilized cell culture models of HRD cancers.
- Employed chemical and genetic inhibition of autophagy-related proteins, including TEX264 and p97 (VCP).
- Assessed PARP1 trapping, nucleophagy, protein aggregation, DNA damage, and cell viability using biochemical and imaging techniques.
Main Results:
- Demonstrated that trapped PARP1 is cleared from chromatin via nucleophagy, a selective form of autophagy.
- Identified TEX264 as a selective autophagy receptor that directly binds trapped PARP1 and links it to the autophagosome via LC3.
- Showed that p97 (VCP) acts as a segregase in this process.
- Found that inhibiting nucleophagy (chemically or genetically) increases PARP1 trapping, leading to protein aggregates, DNA damage, and cell death, thereby re-sensitizing resistant cells to PARPi.
Conclusions:
- Nucleophagy, orchestrated by TEX264 and p97, is a critical cytoprotective mechanism that degrades PARPi-induced trapped PARP1.
- Targeting this nucleophagy pathway can overcome PARPi resistance by enhancing PARP1 trapping and subsequent cell lethality.
- This study reveals a novel therapeutic strategy for enhancing the efficacy of PARPi in cancer treatment.
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