Heterogeneous migration routes of DNA triplet repeat slip-outs

Bianco, S. , Hu, T., Henrich, O. and Magennis, S. W. (2022) Heterogeneous migration routes of DNA triplet repeat slip-outs. Biophysical Reports, 2(3), 100070. (doi: 10.1016/j.bpr.2022.100070) (PMID:36299495) (PMCID:PMC9586884)

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Abstract

It is unclear how the length of a repetitive DNA tract determines the onset and progression of repeat expansion diseases (REDs) but the dynamics of secondary DNA structures formed by repeat sequences are believed to play an important role. It was recently shown that three-way DNA junctions containing slip-out hairpins of CAG or CTG repeats and contiguous triplet repeats in the adjacent duplex, displayed single-molecule FRET (smFRET) dynamics that were ascribed to both local conformational motions and longer-range branch migration. Here we explore these so-called "mobile" slip-out structures through a detailed kinetic analysis of smFRET trajectories, and coarse-grained modelling. Despite the apparent structural simplicity, with six FRET states resolvable, most smFRET states displayed biexponential dwell-time distributions, attributed to structural heterogeneity and overlapping FRET states. Coarse-grained modelling for the (CAG)10 repeat slip-out included trajectories that corresponded to a complete round of branch migration; the structured free-energy landscape between slippage events supports the dynamical complexity observed by smFRET. A hairpin slip-out with 40 CAG repeats, which is above the repeat length required for disease in several triplet repeat disorders, displayed smFRET dwell times that were on average double those of 3WJs with 10 repeats. The rate of secondary-structure re-arrangement via branch migration, relative to particular DNA processing pathways, may be an important factor in the expansion of triplet REDs.

Item Type:Articles
Additional Information:T.H. was supported by the China Scholarship Council and by the Biotechnology and Biological Sciences Research Council (Grant No. BB/T003197/1). O.H. acknowledges support from the EPSRC Early Career Research Software Engineer Fellowship Scheme (Grant No. EP/N019180/2).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Magennis, Dr Steven and Bianco, Simona and Hu, Miss Tianyu
Authors: Bianco, S., Hu, T., Henrich, O., and Magennis, S. W.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Biophysical Reports
Publisher:Elsevier (Cell Press)
ISSN:2667-0747
ISSN (Online):2667-0747
Published Online:11 August 2022
Copyright Holders:Copyright © 2022 The Author(s)
First Published:First published in Biophysical Reports 2(3): 100070
Publisher Policy:Reproduced under a Creative Commons license
Data DOI:10.5525/gla.researchdata.1337

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
305917Decoding heparan sulfate-protein interactions: from single molecules to cell mimicsSteven MagennisBiotechnology and Biological Sciences Research Council (BBSRC)BB/T003197/1Chemistry