Journal Article

REV1 inhibition enhances trinucleotide repeat mutagenesis

Chatterjee, Nimrat, Crompton, Andrew, Siegel, Ava, Almstead, Daniel, Reich, Jessica, Lamkin, Erica, Grover, Aarzoo, Kothandaraman, Naveen, Korzhnev, Dmitry, Jang, Hongjun, del Rio-Guerra, Roxana, Zhou, Pei, Lee, Hyejin, Koval, Hannah, Victor, Joshua, Hadden, M. Kyle, Hong, Jiyong, Ikeh, Kanayo

2025

Overview

Trinucleotide repeat instability has been implicated in the pathogenesis of numerous neurodegenerative disorders. While germline expansions destabilize trinucleotide repeats to cause disease anticipation, somatic cell trinucleotide repeat instability drives earlier onset of symptoms and further disease progression. However, the drivers behind these repeat length changes remain unclear. Current models suggest that DNA replication slippage events and the action of genome instability pathways, such as DNA repair, cause trinucleotide repeat mutagenesis. Whether mutagenic polymerases from the translesion synthesis pathway result in trinucleotide repeat instability is unclear. Translesion synthesis polymerases are best at bypassing difficult-to-replicate DNA regions due to bulky lesions or gaps in DNA. While some effects of translesion synthesis polymerases on trinucleotide repeat instability have been explored in lower organisms, evidence in human cells is lacking. Using a quantitative green fluorescent protein (GFP) reporter with expanded CAG repeats, we show that inhibition of the translesion synthesis polymerase REV1 by its inhibitor, JH-RE-06, or siRNA knockdown increases trinucleotide repeat instability and the underlying mutability. These results suggest that REV1 protects trinucleotide repeat length mutagenesis through potential continuous DNA synthesis when replicative polymerases stall ahead of repeat secondary structures. Collectively, we present evidence of the translesion synthesis pathway’s role in trinucleotide repeat instability, with potential implications for understanding mutability mechanisms, disease biology and therapeutic targeting.

• Publisher: The Royal Society Publishing
• Subject: Biology / Cytomegalovirus / Disease / DNA biosynthesis / DNA damage / DNA methylation / DNA Repair / DNA repeat expansion / DNA Replication / Drug therapy / Gene expression / Genomes / Genomic Instability / Green fluorescent protein / Humans / Metabolism / Mutagenesis / Neurodegenerative diseases / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Nucleotidyltransferases - antagonists & inhibitors / Nucleotidyltransferases - genetics / Nucleotidyltransferases - metabolism / Pathogenesis / Polyglutamine / Proteins / siRNA / Therapeutic targets / Toxicity / Trinucleotide repeat diseases / Trinucleotide Repeat Expansion / Trinucleotide Repeats / Y-Family DNA Polymerases