Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints
Broad evidence in the literature supports double-strand breaks (DSBs) as initiators of mitochondrial DNA (mtDNA) deletion mutations. While DNA misalignment during DSB repair is commonly proposed as the mechanism by which DSBs cause deletion mutations, details such as the specific DNA repair errors a...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/160676 |
| _version_ | 1826117573100437504 |
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| author | Lakshmanan, Lakshmi Narayanan Yee, Zhuangli Halliwell, Barry Gruber, Jan Gunawan, Rudiyanto |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Lakshmanan, Lakshmi Narayanan Yee, Zhuangli Halliwell, Barry Gruber, Jan Gunawan, Rudiyanto |
| author_sort | Lakshmanan, Lakshmi Narayanan |
| collection | NTU |
| description | Broad evidence in the literature supports double-strand breaks (DSBs) as initiators of mitochondrial DNA (mtDNA) deletion mutations. While DNA misalignment during DSB repair is commonly proposed as the mechanism by which DSBs cause deletion mutations, details such as the specific DNA repair errors are still lacking. Here, we used DNA hybridization thermodynamics to infer the sequence lengths of mtDNA misalignments that are associated with mtDNA deletions. We gathered and analyzed 9,921 previously reported mtDNA deletion breakpoints in human, rhesus monkey, mouse, rat, and Caenorhabditis elegans. Our analysis shows that a large fraction of mtDNA breakpoint positions can be explained by the thermodynamics of short ≤ 5-nt misalignments. The significance of short DNA misalignments supports an important role for erroneous non-homologous and micro-homology-dependent DSB repair in mtDNA deletion formation. The consistency of the results of our analysis across species further suggests a shared mode of mtDNA deletion mutagenesis. |
| first_indexed | 2024-10-01T04:29:29Z |
| format | Journal Article |
| id | ntu-10356/160676 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:29:29Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1606762023-03-05T16:52:14Z Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints Lakshmanan, Lakshmi Narayanan Yee, Zhuangli Halliwell, Barry Gruber, Jan Gunawan, Rudiyanto Lee Kong Chian School of Medicine (LKCMedicine) National University of Singapore Science::Medicine Bioinformatics Molecular Genetics Broad evidence in the literature supports double-strand breaks (DSBs) as initiators of mitochondrial DNA (mtDNA) deletion mutations. While DNA misalignment during DSB repair is commonly proposed as the mechanism by which DSBs cause deletion mutations, details such as the specific DNA repair errors are still lacking. Here, we used DNA hybridization thermodynamics to infer the sequence lengths of mtDNA misalignments that are associated with mtDNA deletions. We gathered and analyzed 9,921 previously reported mtDNA deletion breakpoints in human, rhesus monkey, mouse, rat, and Caenorhabditis elegans. Our analysis shows that a large fraction of mtDNA breakpoint positions can be explained by the thermodynamics of short ≤ 5-nt misalignments. The significance of short DNA misalignments supports an important role for erroneous non-homologous and micro-homology-dependent DSB repair in mtDNA deletion formation. The consistency of the results of our analysis across species further suggests a shared mode of mtDNA deletion mutagenesis. Published version We acknowledged financial support from ETH Zurich, Switzerland (LN) and Swiss National Science Foundation, Switzerland (grant number 150522; JG and RG). 2022-08-01T01:01:04Z 2022-08-01T01:01:04Z 2021 Journal Article Lakshmanan, L. N., Yee, Z., Halliwell, B., Gruber, J. & Gunawan, R. (2021). Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints. IScience, 24(3), 102138-. https://dx.doi.org/10.1016/j.isci.2021.102138 2589-0042 https://hdl.handle.net/10356/160676 10.1016/j.isci.2021.102138 33665557 2-s2.0-85101041010 3 24 102138 en iScience © 2021 The Authors. This is an open access article under the CC BY license http://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Science::Medicine Bioinformatics Molecular Genetics Lakshmanan, Lakshmi Narayanan Yee, Zhuangli Halliwell, Barry Gruber, Jan Gunawan, Rudiyanto Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints |
| title | Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints |
| title_full | Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints |
| title_fullStr | Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints |
| title_full_unstemmed | Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints |
| title_short | Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints |
| title_sort | thermodynamic analysis of dna hybridization signatures near mitochondrial dna deletion breakpoints |
| topic | Science::Medicine Bioinformatics Molecular Genetics |
| url | https://hdl.handle.net/10356/160676 |
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