REV1 inhibition enhances trinucleotide repeat mutagenesis

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Trinucleotide repeat (TNR) instability is a key factor in neurodegenerative diseases.
• Somatic cell TNR instability contributes to disease onset and progression.
• The precise mechanisms driving TNR instability remain largely unknown.

Purpose of the Study:

• To investigate the role of translesion synthesis (TLS) polymerases in TNR instability in human cells.
• To determine if REV1, a TLS polymerase, influences TNR mutagenesis.

Main Methods:

• Utilized a quantitative GFP reporter assay with expanded CAG repeats in human cells.
• Inhibited REV1 activity using a specific inhibitor (JH-RE-06).
• Reduced REV1 expression via siRNA knockdown.

Main Results:

• Inhibition or knockdown of REV1 significantly increased TNR instability and mutability.
• These findings suggest REV1 plays a protective role in maintaining TNR length.
• REV1 may facilitate DNA synthesis past stalled replicative polymerases at repeat regions.

Conclusions:

• The translesion synthesis (TLS) pathway, specifically REV1, is implicated in regulating trinucleotide repeat (TNR) instability.
• REV1 appears to protect against TNR mutagenesis, potentially by aiding DNA replication through challenging repeat sequences.
• These findings offer insights into TNR mutability mechanisms and suggest potential therapeutic avenues for neurodegenerative disorders.