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Published on: January 26, 2018
Methylation by Set9 modulates FoxO3 stability and transcriptional activity
Daniel R Calnan1, Ashley E Webb, Jamie L White
1Cancer Biology Program, Stanford University, CA 94305, USA.
Aging
|July 24, 2012
Summary
This study reveals that Set9 methyltransferase directly modifies FoxO3, impacting its stability and transcriptional activity. This methylation is crucial for cellular stress responses, potentially influencing longevity and tumor suppression.
Area of Science:
- Molecular Biology
- Epigenetics
- Cellular Biology
Background:
- The FoxO family, particularly FoxO3, is vital for longevity and tumor suppression.
- FoxO3 activity is regulated by post-translational modifications, forming a 'code' that influences its function.
- Lysine methylation is a key epigenetic modification, but its role in FoxO3 regulation was unknown.
Purpose of the Study:
- To investigate whether lysine methylation modulates FoxO3 activity.
- To identify the specific methyltransferase and site involved in FoxO3 methylation.
- To understand the functional consequences of FoxO3 methylation on protein stability and transcriptional activity.
Main Methods:
- In vitro and in-cell methylation assays using the methyltransferase Set9.
- Tandem mass spectrometry to identify methylated residues.
- Methyl-specific antibodies to detect methylation.
- Analysis of FoxO3 protein stability and transcriptional activity.
Main Results:
- Set9 directly methylates FoxO3 at lysine 271.
- This methylation site (K271) was previously known to be deacetylated by Sirt1.
- Set9-mediated methylation decreases FoxO3 protein stability but moderately increases its transcriptional activity.
Conclusions:
- Lysine methylation by Set9 is a novel post-translational modification of FoxO3.
- Methylation fine-tunes FoxO3 stability and activity, impacting cellular stress responses.
- This regulatory mechanism may contribute to FoxO3's roles in tumor suppression and longevity.
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