Related Experiment Video
Updated: Nov 9, 2025
11:25
A G-quadruplex DNA-affinity Approach for Purification of Enzymatically Active G4 Resolvase1
Published on: March 18, 2017
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A Helicase Unwinds Hexanucleotide Repeat RNA G-Quadruplexes and Facilitates Repeat-Associated Non-AUG Translation
Honghe Liu1,2, Yu-Ning Lu1,2, Tapas Paul3
1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, United States.
Journal of the American Chemical Society
|April 15, 2021
Summary
The RNA helicase DHX36 promotes toxic protein production in C9orf72-linked ALS and FTD by unwinding G-quadruplex structures in repeat RNA. Reducing DHX36 lowers these toxic proteins, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The C9orf72 gene hexanucleotide repeat expansion is a leading cause of ALS and FTD.
- Repeat-associated non-AUG (RAN) translation produces toxic dipeptide repeat (DPR) proteins, but its regulation is unclear.
Purpose of the Study:
- Investigate the role of RNA helicase DHX36 in C9orf72 repeat-associated RAN translation.
- Determine if DHX36 is a potential therapeutic target for C9orf72-linked ALS and FTD.
Main Methods:
- Assessed DHX36 binding affinity and unwinding activity on G4C2 repeat RNA.
- Examined DHX36's interaction with G4C2 RNA in cellular models.
- Reduced DHX36 levels in patient-derived iPSCs and motor neurons.
- Measured DPR protein levels in cells with altered DHX36 expression.
- Analyzed DHX36 expression in patient tissues.
Main Results:
- DHX36 binds G4C2 repeat RNA, particularly its G-quadruplex form, and unwinds these structures.
- DHX36 is essential for C9orf72 RAN translation.
- Reducing DHX36 in patient-derived cells decreased DPR protein levels.
- DHX36 is upregulated in C9orf72-linked ALS patient tissues.
Conclusions:
- DHX36 acts as a positive regulator of C9orf72 RAN translation by resolving G-quadruplex structures.
- DHX36 is a potential therapeutic target for C9orf72-linked ALS and FTD.
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