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PRMT5 regulates ATF4 transcript splicing and oxidative stress response.

Magdalena M Szewczyk1, Genna M Luciani2, Victoria Vu3

  • 1Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.

Redox Biology
|March 19, 2022
PubMed
Summary
This summary is machine-generated.

Protein methyltransferase 5 (PRMT5) regulates transcription and splicing. PRMT5 inhibition impacts the ATF4 pathway in AML, affecting oxidative stress and cellular growth, particularly in EVI1-overexpressing leukemia.

Keywords:
ATF4EVI1EpigeneticsIntron retentionOxidative stressPRMT5Splicing

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Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Protein methyltransferase 5 (PRMT5) is a key regulator of transcription and splicing.
  • PRMT5 is an emerging target in oncology, but its dependency mechanisms in cancer are not fully understood.
  • The activating transcription factor 4 (ATF4) pathway plays a role in cellular stress responses.

Purpose of the Study:

  • To investigate the role of PRMT5 in acute myelogenous leukemia (AML).
  • To elucidate the molecular mechanisms linking PRMT5 to cancer cell dependency.
  • To explore the interplay between PRMT5, ATF4, and oxidative stress in AML, especially in the context of EVI1 overexpression.

Main Methods:

  • Transcriptomic analysis to identify PRMT5-regulated pathways in AML.
  • Assessment of ATF4 mRNA stability and localization upon PRMT5 inhibition.
  • Evaluation of cellular responses including oxidative stress, growth arrest, and senescence.
  • Correlation analysis of EVI1 and ATF4 expression signatures.

Main Results:

  • PRMT5 inhibition leads to unstable, nuclear-retained ATF4 mRNA and reduced ATF4 protein levels.
  • Loss of PRMT5 function in AML cells with low ATF4 results in oxidative stress, growth arrest, and senescence.
  • Leukemia cells overexpressing EVI1 show dependence on PRMT5 and have reduced ATF4 levels.
  • EVI1-high AML cells exhibit elevated baseline reactive oxygen species and increased sensitivity to PRMT5 inhibition.

Conclusions:

  • The PRMT5-ATF4 axis is crucial for maintaining cellular redox balance, particularly in high oxidative stress conditions.
  • EVI1-high AML cells are dependent on PRMT5 for managing oxidative stress.
  • Targeting PRMT5 may be a viable strategy for treating specific subtypes of AML characterized by EVI1 overexpression.