Mitochondrial DNA exhibits resistance to induced point and deletion mutations.
Mitochondrial DNA exhibits resistance to induced point and deletion mutations.
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DOI：
10.1093/nar/gkw716
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发表时间：
2016-10-14
影响因子：
14.9
通讯作者：
Bielas JH
中科院分区：
文献类型：
--
作者：
Valente WJ;Ericson NG;Long AS;White PA;Marchetti F;Bielas JH
体细胞线粒体DNA（mtDNA）突变的积累有助于人类疾病的发病机制。目前，线粒体突变在很大程度上被认为是对其严重受损的基因组进行不准确处理的结果。然而，主要是由于缺乏足够灵敏度和准确性的监测mtDNA突变的方法，mtDNA损伤和突变之间的联系尚未建立。为了验证mtDNA损伤剂诱导mtDNA突变的假设，我们将MutaTMmouse小鼠暴露于苯并[a]芘（B [a] P）或N-乙基-N-亚硝基脲（ENU），每天连续28天，并使用我们新开发的数字随机突变捕获（dRMC）和数字缺失检测（3D）分析定量骨髓和肝脏中的mtDNA点突变和缺失突变。令人惊讶的是，我们的结果表明诱变剂处理并没有增加线粒体点突变或缺失突变频率，尽管有证据表明两种化合物都增加了核DNA突变，并证明了mtDNA中B [a] P加合物的形成。这些发现与mtDNA突变模型相矛盾，该模型认为mtDNA突变率的升高源于损伤敏感性和缩短的修复能力。相反，我们的研究结果表明，诱导的mtDNA损伤不容易转化为突变。这些发现表明，强大的线粒体损伤反应抑制诱变剂暴露后诱导的突变。
The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaTMMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure.
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影响因子：
14.9
作者：
Bess AS;Crocker TL;Ryde IT;Meyer JN
通讯作者：
Meyer JN
影响因子：
4.1
作者：
DIZDAROGLU, M;HOLWITT, E;BLAKELY, WF
通讯作者：
BLAKELY, WF
DOI：
10.1073/pnas.86.20.7971
发表时间：
1989-10-01
影响因子：
11.1
作者：
GOSSEN, JA;DELEEUW, WJF;VIJG, J
通讯作者：
VIJG, J
DOI：
10.1111/j.1532-5415.1972.tb00787.x
发表时间：
1972-01-01
影响因子：
6.3
作者：
HARMAN, D
通讯作者：
HARMAN, D
影响因子：
14.9
作者：
Graziewicz, MA;Sayer, JM;Copeland, WC
通讯作者：
Copeland, WC