Genome-Wide CRISPR Screen Reveals Autophagy Disruption as the Convergence Mechanism That Regulates the NRF2

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Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
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Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes

Published on: May 23, 2025

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Michael J Kerins1, Pengfei Liu1, Wang Tian1

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.

Molecular and Cellular Biology
|April 24, 2019
PubMed

Insights

A genome-wide screen identified 273 genes that activate nuclear factor (erythroid 2)-like 2 (NRF2). Eight high-confidence NRF2 negative regulators, including several involved in autophagy, were validated, revealing a link between autophagy and NRF2.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • Nuclear factor (erythroid 2)-like 2 (NRF2) is a transcription factor crucial for cellular homeostasis.
  • NRF2 deregulation is linked to diseases like cancer and neurodegeneration.
  • A complete regulatory network for NRF2 remains elusive.

Purpose of the Study:

  • To identify novel regulators of NRF2.
  • To elucidate the relationship between NRF2 and other cellular processes.

Main Methods:

  • Genome-wide CRISPR screen to identify NRF2 activators.
  • Pathway analysis to identify enriched biological processes.
  • Molecular validation of candidate NRF2 regulators.

Main Results:

  • A CRISPR screen identified 273 genes whose knockout leads to sustained NRF2 activation.
  • Pathway analysis revealed autophagy-related genes are significantly overrepresented.
  • Eight high-confidence NRF2 negative regulators were validated, including ATG12, ATG7, KEAP1, and VPS37A, which are involved in autophagy.

Conclusions:

  • This study presents a comprehensive list of NRF2 negative regulators.
  • An intimate link between autophagy and NRF2 regulation is revealed.
Keywords:
CRISPRKEAP1NFE2L2NRF2autophagygene reportersgenomicsmolecular biologyoxidative stresssignal transduction

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