Friedreich's ataxia–associated GAA repeats induce replication-fork reversal and unusual molecular junctions

Friedreich's ataxia is one of several hereditary neurodegenerative disorders caused expansion of trinucleotide repeats, but the mechanism of their genomic propagation is unknown. A new plasmid-based system to probe human replicative intermediates reveals that GAA/TTC repeats interfere with repl...

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Vydáno v:Nature structural & molecular biology Ročník 20; číslo 4; s. 486 - 494
Hlavní autoři: Follonier, Cindy, Oehler, Judith, Herrador, Raquel, Lopes, Massimo
Médium: Journal Article
Jazyk:angličtina
Vydáno: New York Nature Publishing Group US 01.04.2013
Nature Publishing Group
Témata:
631/337/151
631/378/1689/2014
631/45/535
Ataxia
Biochemistry
Biological Microscopy
Care and treatment
Crystal structure
DNA Replication
Electrophoresis
Friedreich Ataxia - genetics
Genetic aspects
Genetic disorders
Humans
Life Sciences
Membrane Biology
Molecular biology
Neurodegeneration
Plasmids
Protein Structure
Repetitive Sequences, Nucleic Acid
Signal transduction
Switzerland
ISSN:1545-9993, 1545-9985, 1545-9985
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Shrnutí:Friedreich's ataxia is one of several hereditary neurodegenerative disorders caused expansion of trinucleotide repeats, but the mechanism of their genomic propagation is unknown. A new plasmid-based system to probe human replicative intermediates reveals that GAA/TTC repeats interfere with replication, thus suggesting that repeat expansion occurs by postreplicative mechanisms. Expansion of GAA/TTC repeats is the causative event in Friedreich's ataxia. GAA repeats have been shown to hinder replication in model systems, but the mechanisms of replication interference and expansion in human cells remained elusive. To study in vivo replication structures at GAA repeats, we designed a new plasmid-based system that permits the analysis of human replication intermediates by two-dimensional gel electrophoresis and EM. We found that replication forks transiently pause and reverse at long GAA/TTC tracts in both orientations. Furthermore, we identified replication-associated intramolecular junctions, located between GAA/TTC repeats and other homopurine-homopyrimidine tracts, that were associated with breakage of the plasmid fork not traversing the repeats. Finally, we detected postreplicative, sister-chromatid hemicatenanes on control plasmids, which were replaced by persistent homology-driven junctions at GAA/TTC repeats. These data prove that GAA/TTC tracts interfere with replication in humans and implicate postreplicative mechanisms in trinucleotide repeat expansion.
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ISSN:1545-9993
1545-9985
1545-9985
DOI:10.1038/nsmb.2520