Heterogeneous migration routes of DNA triplet repeat slip-outs

Bianco, Simona; Hu, Tianyu; Henrich, Oliver; Magennis, Steven W.

doi:10.1016/j.bpr.2022.100070

Cited by 2 publications

(1 citation statement)

References 74 publications

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“…2 , should allow one to determine if the presence of the repeat disruption indeed influences rollamer loop distribution, as hypothesised here; thereby reducing the effective repeat length. Single-molecule studies may prove useful in this regard (Hu et al, 2021 ; Bianco et al, 2022 ). Finally, it may be possible to test the extent to which the mismatch repair system is able to repair the repeat disruption by using a site specifically located mismatch at the repeat /nonrepeat DNA sequence junction in a rollameric system.…”

Section: Going Forward: Potential Experimental Assessments Of the Pro...mentioning

confidence: 99%

How sequence alterations enhance the stability and delay expansion of DNA triplet repeat domains

Völker,

Breslauer

2023

QRB Discovery

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DNA sequence alterations within DNA repeat domains inexplicably enhance the stability and delay the expansion of interrupted repeat domains. Here we propose mechanisms that rationalise such unanticipated outcomes. Specifically, we describe how interruption of a DNA repeat domain restricts the ensemble space available to dynamic, slip out, repeat bulge loops by introducing energetic barriers to loop migration. We explain how such barriers arise because some possible loop isomers result in energetically costly mismatches in the duplex portion of the repeat domain. We propose that the reduced ensemble space is the causative feature for the observed delay in repeat DNA expansion. We further posit that the observed loss of the interrupting repeat in some expanded DNAs reflects the transient occupation of loop isomer positions that result in a mismatch in the duplex stem due to ‘leakiness’ in the energy barrier. We propose that if the lifetime of such a low probability event allows for recognition by the mismatch repair system, then ‘repair’ of the repeat interruption can occur; thereby rationalising the absence of the interruption in the final expanded DNA ‘product.’ Our proposed mechanistic pathways provide reasoned explanations for what have been described as ‘puzzling’ observations, while also yielding insights into a biomedically important set of coupled genotypic phenomena that map the linkage between DNA origami thermodynamics and phenotypic disease states.

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Section: Going Forward: Potential Experimental Assessments Of the Pro...mentioning

confidence: 99%

How sequence alterations enhance the stability and delay expansion of DNA triplet repeat domains

Völker,

Breslauer

2023

QRB Discovery

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A single CAA interrupt in a DNA three-way junction containing a CAG repeat hairpin results in parity-dependent trapping

Cadden,

Wilken,

Magennis

2024

Nucleic Acids Research

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An increasing number of human disorders are attributed to genomic expansions of short tandem repeats (STRs). Secondary DNA structures formed by STRs are believed to play an important role in expansion, while the presence of nucleotide interruptions within the pure repeat sequence is known to delay the onset and progression of disease. We have used two single-molecule fluorescence techniques to analyse the structure and dynamics of DNA three-way junctions (3WJs) containing CAG repeat hairpin slipouts, with and without a single CAA interrupt. For a 3WJ with a (CAG)10 slipout, the CAA interrupt is preferentially located in the hairpin loop, and the branch migration dynamics are 4-fold slower than for the 3WJ with a pure (CAG)10, and 3-fold slower than a 3WJ with a pure (CAG)40 repeat. The (CAG)11 3WJ with CAA interrupt adopts a conformation that places the interrupt in or near the hairpin loop, with similar dynamics to the pure (CAG)10 and (CAG)11 3WJs. We have shown that changing a single nucleotide (G to A) in a pure repeat can have a large impact on 3WJ structure and dynamics, which may be important for the protective role of interrupts in repeat expansion diseases.

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Heterogeneous migration routes of DNA triplet repeat slip-outs

Cited by 2 publications

References 74 publications

How sequence alterations enhance the stability and delay expansion of DNA triplet repeat domains

How sequence alterations enhance the stability and delay expansion of DNA triplet repeat domains

A single CAA interrupt in a DNA three-way junction containing a CAG repeat hairpin results in parity-dependent trapping

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