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RTEL1 inhibits trinucleotide repeat expansions and fragility
Aisling Frizzell1, Jennifer H G Nguyen2, Mark I R Petalcorin3
1Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Newcastle Road, Galway, Ireland.
Cell Reports
|February 25, 2014
Summary
The DNA helicase RTEL1 prevents harmful trinucleotide repeat expansions, a key cause of 17 neurological diseases. This finding suggests RTEL1 is crucial for preventing genetic instability and related disorders.
Area of Science:
- Genetics
- Molecular Biology
- Human Health
Background:
- RTEL1 is a vital human helicase involved in telomere maintenance and DNA repair.
- Trinucleotide repeat expansions are linked to numerous inherited neurological disorders.
Purpose of the Study:
- To investigate the role of RTEL1 in preventing trinucleotide repeat expansions.
- To explore the mechanism by which RTEL1 inhibits these expansions.
Main Methods:
- Knockdown of RTEL1 in human cells.
- In vitro biochemical assays using purified RTEL1 and triplet repeat hairpins.
- Functional analysis in yeast models comparing RTEL1 and Fbh1.
Main Results:
- RTEL1 knockdown increased (CTG⋅CAG) repeat expansion frequencies in human cells.
- Purified RTEL1 unwound triplet repeat hairpins in vitro.
- RTEL1's expansion-blocking activity required Rad18 and HLTF.
- RTEL1 suppressed expansions and fragility in yeast srs2 mutants.
Conclusions:
- RTEL1 acts as a crucial guardian against trinucleotide repeat expansions.
- RTEL1 likely inhibits expansions by unwinding problematic hairpin structures.
- RTEL1 functions analogously to yeast Srs2 in preventing repeat expansions and fragility.
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