Heterogeneous migration routes of DNA triplet repeat slip-outs

Bianco, Simona and Hu, Tianhu and Henrich, Oliver and Magennis, Steven W. (2022) Heterogeneous migration routes of DNA triplet repeat slip-outs. Biophysical Reports, 2 (3). 100070. (https://doi.org/10.1016/j.bpr.2022.100070)

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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, 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 modeling. 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 modeling for a (GAC)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 rearrangement via branch migration, relative to particular DNA processing pathways, may be an important factor in the expansion of triplet repeat expansion diseases.

  • Item type:Article
    ID code:82114
    Dates:
    Date
    Event
    14 September 2022
    Published
    27 August 2022
    Published Online
    8 August 2022
    Accepted
    Subjects:Science > Physics
    Department:Faculty of Science > Physics
    Depositing user: Pure Administrator
    Date deposited:29 Aug 2022 14:02
    Last modified:09 Apr 2024 03:28
    URI:https://strathprints.strath.ac.uk/id/eprint/82114
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