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Related Concept Videos

Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...
Phagocytosis of Apoptotic Cells01:17

Phagocytosis of Apoptotic Cells

Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or  immature dendritic cells. Non-professional phagocytes such as  epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes. 
Normal cells contain receptors that prevent them from being recognized by phagocytes.
Autophagy01:27

Autophagy

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart, a...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...

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Related Experiment Video

Updated: Jun 4, 2026

Visualization and Quantitative Analysis of Genotoxin-Induced PARP1/PARP2 Activation in Cells Using a Fluorescent Fusion Protein-Based Reporter
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Visualization and Quantitative Analysis of Genotoxin-Induced PARP1/PARP2 Activation in Cells Using a Fluorescent Fusion Protein-Based Reporter

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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
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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.

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Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy

Published on: May 4, 2016

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.