PRMT5 regulates ATF4 transcript splicing and oxidative stress response

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.