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Updated: Oct 6, 2025
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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
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To Degrade or Not to Degrade DNMT3A
Yuhong Ma1, Britta Will2,3
1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.
Cancer Discovery
|January 13, 2022
Summary
Aberrant DNA methylation, linked to aging and cancer, can be driven by new DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) variants. These variants show reduced activity due to degradation, promoting stem cell expansion.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Mechanisms of Aging
- Hematopoiesis and Stem Cell Biology
Background:
- Aberrant DNA cytosine methylation is implicated in aging, impaired tissue regeneration, and cancer development.
- DNA methyltransferases play crucial roles in establishing and maintaining methylation patterns.
- Dysregulation of DNA methyltransferases, particularly DNMT3A, is associated with various cancers.
Purpose of the Study:
- To identify and characterize novel disease-associated variants of DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A).
- To investigate the impact of these variants on de novo DNA methylation activity and protein stability.
- To determine the role of these DNMT3A variants in the clonal expansion of hematopoietic stem cells.
Main Methods:
- Variant analysis of DNMT3A in disease contexts.
- Biochemical assays to measure de novo DNA methylation activity.
- Assessment of protein stability and proteasomal degradation pathways.
- In vitro and in vivo studies using hematopoietic stem cells.
Main Results:
- A new class of DNMT3A variants was identified, associated with disease.
- These variants exhibit significantly decreased de novo DNA methylation activity.
- Increased proteasomal degradation of these variants was observed, leading to reduced protein levels.
- The identified DNMT3A variants promote the clonal expansion of hematopoietic stem cells.
Conclusions:
- Novel DNMT3A variants contribute to disease pathogenesis through impaired DNA methylation and stem cell expansion.
- Proteasomal degradation is a key mechanism regulating the activity of these disease-associated DNMT3A variants.
- Targeting DNMT3A stability or activity may offer therapeutic strategies for age-related diseases and cancers.
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