Mitochondrial DNA deletions are associated with non-B DNA conformations.
Mitochondrial DNA deletions are associated with non-B DNA conformations.
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DOI：
10.1093/nar/gks500
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发表时间：
2012-09
影响因子：
14.9
通讯作者：
Pereira F
中科院分区：
文献类型：
--
作者：
Damas J;Carneiro J;Gonçalves J;Stewart JB;Samuels DC;Amorim A;Pereira F
线粒体DNA（mtDNA）缺失是线粒体疾病的主要原因，并且被认为有助于衰老过程和各种神经退行性疾病。尽管有强有力的观察和实验证据，但删除过程的分子基础仍然不清楚。在这项研究中，我们测试的假设，即mtDNA的脆弱性断裂的主要原因在于非B DNA构象，即发夹，十字形和苜蓿叶样元素的形成。使用迄今为止建立的最大的人类mtDNA缺失数据库（753个不同的病例），我们发现mtDNA中存在位点特异性断裂热点。此外，我们发现最常见的缺失断点发生在预测结构内或附近，这一结果得到了患有线粒体疾病的转基因小鼠数据的支持。线粒体DNA区域的折叠能和它所包含的断裂点的数量之间也有显著的关联。特别是，两簇发夹（靠近D环3′-末端和L链复制起点）是mtDNA断裂的热点。与我们的假设一致，在高度结构化的tRNA基因中发现了每个碱基的5′-和3′-断裂点的最高数量。总的来说，本研究中的数据表明，非B DNA构象是mtDNA缺失过程的关键因素。
Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are believed to contribute to the aging process and to various neurodegenerative diseases. Despite strong observational and experimental evidence, the molecular basis of the deletion process remains obscure. In this study, we test the hypothesis that the primary cause of mtDNA vulnerability to breakage resides in the formation of non-B DNA conformations, namely hairpin, cruciform and cloverleaf-like elements. Using the largest database of human mtDNA deletions built thus far (753 different cases), we show that site-specific breakage hotspots exist in the mtDNA. Furthermore, we discover that the most frequent deletion breakpoints occur within or near predicted structures, a result that is supported by data from transgenic mice with mitochondrial disease. There is also a significant association between the folding energy of an mtDNA region and the number of breakpoints that it harbours. In particular, two clusters of hairpins (near the D-loop 3′-terminus and the L-strand origin of replication) are hotspots for mtDNA breakage. Consistent with our hypothesis, the highest number of 5′- and 3′-breakpoints per base is found in the highly structured tRNA genes. Overall, the data presented in this study suggest that non-B DNA conformations are a key element of the mtDNA deletion process.
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