Conformational and migrational dynamics of slipped-strand DNA three-way junctions containing trinucleotide repeats

Hu, T., Morten, M. J. and Magennis, S. M. (2021) Conformational and migrational dynamics of slipped-strand DNA three-way junctions containing trinucleotide repeats. Nature Communications, 12, 204. (doi: 10.1038/s41467-020-20426-3) (PMID:33420051) (PMCID:PMC7794359)

Abstract

Expansions of CAG/CTG trinucleotide repeats in DNA are the cause of at least 17 degenerative human disorders, including Huntington’s Disease. Repeat instability is thought to occur via the formation of intrastrand hairpins during replication, repair, recombination, and transcription though relatively little is known about their structure and dynamics. We use single-molecule Förster resonance energy transfer to study DNA three-way junctions (3WJs) containing slip-outs composed of CAG or CTG repeats. 3WJs that only have repeats in the slip-out show two-state behavior, which we attribute to conformational flexibility at the 3WJ branchpoint. When the triplet repeats extend into the adjacent duplex, additional dynamics are observed, which we assign to interconversion of positional isomers. We propose a branchpoint migration model that involves conformational rearrangement, strand exchange, and bulge-loop movement. This migration has implications for how repeat slip-outs are processed by the cellular machinery, disease progression, and their development as drug targets.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hu, Miss Tianyu and Magennis, Dr Steven and Morten, Dr Michael
• Authors: Hu, T., Morten, M. J., and Magennis, S. M.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12(1):204
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
170215		From nature to nano: structure, dynamics and reactivity of DNA three-way junctions	Steven Magennis	Engineering and Physical Sciences Research Council (EPSRC)	EP/L027003/1	Chemistry