文章基本信息

标题：Thermodynamic analysis of DNA hybridization signatures near mitochondrial DNA deletion breakpoints
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作者：Lakshmi Narayanan Lakshmanan ; Zhuangli Yee ; Barry Halliwell 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：3
页码：1-31
DOI：10.1016/j.isci.2021.102138
语种：English
出版社：Elsevier
摘要：SummaryBroad 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, andCaenorhabditis 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.Graphical abstractDisplay OmittedHighlights•We analyzed DNA hybridization signatures of 9921 mtDNA deletions in 5 species•A large fraction of mtDNA deletions exhibit short ≤5-nt misalignment signatures•Our results point to erroneous non-homologous DNA end-joining repair in mutagenesis•The agreement of results across species suggests similar deletion mutagenesisMolecular Genetics; Bioinformatics; Sequence Analysis