Heterogeneous migration routes of DNA triplet repeat slip-outs
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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | Biophysical Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667074722000271 |
| _version_ | 1811183263594577920 |
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| author | Simona Bianco Tianyu Hu Oliver Henrich Steven W. Magennis |
| author_facet | Simona Bianco Tianyu Hu Oliver Henrich Steven W. Magennis |
| author_sort | Simona Bianco |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:45:07Z |
| format | Article |
| id | doaj.art-2df4a8e74b124d479b112cef3f96548e |
| institution | Directory Open Access Journal |
| issn | 2667-0747 |
| language | English |
| last_indexed | 2024-04-11T09:45:07Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biophysical Reports |
| spelling | doaj.art-2df4a8e74b124d479b112cef3f96548e2022-12-22T04:31:05ZengElsevierBiophysical Reports2667-07472022-09-0123100070Heterogeneous migration routes of DNA triplet repeat slip-outsSimona Bianco0Tianyu Hu1Oliver Henrich2Steven W. Magennis3School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UKSchool of Chemistry, University of Glasgow, Glasgow G12 8QQ, UKDepartment of Physics, University of Strathclyde, Glasgow G4 0NG, UK; Corresponding authorSchool of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK; Corresponding authorIt 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.http://www.sciencedirect.com/science/article/pii/S2667074722000271 |
| spellingShingle | Simona Bianco Tianyu Hu Oliver Henrich Steven W. Magennis Heterogeneous migration routes of DNA triplet repeat slip-outs Biophysical Reports |
| title | Heterogeneous migration routes of DNA triplet repeat slip-outs |
| title_full | Heterogeneous migration routes of DNA triplet repeat slip-outs |
| title_fullStr | Heterogeneous migration routes of DNA triplet repeat slip-outs |
| title_full_unstemmed | Heterogeneous migration routes of DNA triplet repeat slip-outs |
| title_short | Heterogeneous migration routes of DNA triplet repeat slip-outs |
| title_sort | heterogeneous migration routes of dna triplet repeat slip outs |
| url | http://www.sciencedirect.com/science/article/pii/S2667074722000271 |
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