REV1 inhibition enhances trinucleotide repeat mutagenesis.
Ava Siegel1, Daniel Almstead2, Naveen Kothandaraman2
1University of Vermont Larner College of Medicine , Burlington, VT, USA.
Open Biology
|January 15, 2026
Summary
The translesion synthesis polymerase REV1 protects against trinucleotide repeat instability. Inhibiting REV1 increases repeat mutations, suggesting a role in preventing neurodegenerative disease progression.
Area of Science:
- Genetics
- Molecular Biology
- Neuroscience
Background:
- Trinucleotide repeat instability is central to neurodegenerative diseases.
- Somatic instability drives disease progression, but its causes are unclear.
- DNA replication slippage and repair pathways are suspected drivers.
Purpose of the Study:
- To investigate the role of translesion synthesis (TLS) polymerases in trinucleotide repeat instability in human cells.
- To determine if REV1, a TLS polymerase, influences trinucleotide repeat mutagenesis.
Main Methods:
- Utilized a quantitative green fluorescent protein (GFP) reporter assay with expanded CAG repeats.
- Inhibited the TLS polymerase REV1 using a specific inhibitor (JH-RE-06).
- Performed siRNA knockdown of REV1 to assess its function.
Main Results:
- Inhibition or knockdown of REV1 significantly increased trinucleotide repeat instability.
- REV1 inhibition led to higher mutability at expanded CAG repeat sequences.
- These findings indicate REV1 plays a protective role against repeat length changes.
Conclusions:
- The translesion synthesis pathway, specifically REV1, is involved in maintaining trinucleotide repeat stability.
- REV1 may prevent repeat mutagenesis by facilitating DNA synthesis past stalled replicative polymerases.
- Understanding REV1's role offers potential therapeutic targets for trinucleotide repeat disorders.
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