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bioRxiv · 10.1101/254631

Thermodynamic analysis of mitochondrial DNA breakpoints reveals mechanistic details of deletion mutagenesis

Lakshmanan, L. N.·Yee, Z.·Gruber, J.·Halliwell, B.·Gunawan, R.
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Abstract

Broad evidence support double-strand breaks (DSBs) as initiators of mitochondrial DNA (mtDNA) deletion mutations. But the mechanism of DSB-induced deletions, including the DSB repair pathway(s) involved, remains to be established. Here, we used DNA hybridization thermodynamics to analyze misalignment lengths surrounding deletion breakpoints. Our analysis of 9,655 previously reported mammalian mtDNA deletions and 1,307 novel Caenorhabditis elegans mtDNA deletions, indicates a significant role of 0-25bp misalignments, supporting the role of erroneous non-homologous and micro-homology dependent DSB repair in deletion formation. Based on these insights we propose that DSB-induced mtDNA deletions occur via the misjoining of DSB ends and/or strand invasion of open mtDNA regions by DSB ends.

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Lakshmanan, L. N., Yee, Z., Gruber, J., Halliwell, B., Gunawan, R.. 2018-01-27. Thermodynamic analysis of mitochondrial DNA breakpoints reveals mechanistic details of deletion mutagenesis. https://doi.org/10.1101/254631

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