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Updated: Aug 20, 2025
09:13
Generation of Cancer Cell Clones to Visualize Telomeric Repeat-containing RNA TERRA Expressed from a Single Telomere in Living Cells
Published on: January 17, 2019
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METTL3-mediated m6A modification stabilizes TERRA and maintains telomere stability
Liping Chen1,2, Canfeng Zhang3, Wenbin Ma1
1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Nucleic Acids Research
|November 18, 2022
Summary
The study reveals that METTL3 enzyme modifies telomeric repeat-containing RNA (TERRA) with m6A, stabilizing it and protecting telomere length. Loss of METTL3 destabilizes telomeres, offering a potential therapeutic target for alternative lengthening of telomeres (ALT) cancers.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Telomeric repeat-containing RNA (TERRA) is crucial for telomere stability, forming R-loops that require precise regulation.
- Dysregulation of R-loops, either excessive or insufficient, leads to telomere instability.
Purpose of the Study:
- To investigate the role of m6A modification in TERRA stability and its impact on telomere maintenance.
- To elucidate the mechanism by which METTL3 influences TERRA and telomere stability.
Main Methods:
- Analysis of m6A modification on TERRA.
- Investigating the function of METTL3 and YTHDC1 in TERRA regulation.
- Assessing telomere stability and R-loop formation upon METTL3 or YTHDC1 knockdown.
Main Results:
- m6A modification is present on subtelomeric regions of TERRA, mediated by METTL3 and recognized by YTHDC1, stabilizing TERRA.
- Loss of METTL3 or YTHDC1 leads to increased TERRA degradation and telomere instability.
- m6A-modified TERRA promotes R-loop formation and homologous recombination, essential for the alternative lengthening of telomeres (ALT) pathway in cancer cells.
Conclusions:
- METTL3 protects telomeres by catalyzing m6A modification on TERRA, thereby stabilizing it.
- METTL3 depletion results in reduced R-loops, telomere shortening, and instability.
- Targeting METTL3 presents a potential therapeutic strategy for cancers utilizing the ALT pathway.
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