mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae.
mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae.
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mip1 含有与线粒体疾病相关的突变，会导致酿酒酵母中 mtDNA 的突变和耗竭。
DOI：
10.1093/hmg/ddq089
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发表时间：
2010
影响因子：
3.5
通讯作者：
Copeland,WilliamC
中科院分区：
文献类型：
--
作者：
Stumpf,JeffreyD;Bailey,ChristopherM;Spell,Diana;Stillwagon,Matthew;Anderson,KarenS;Copeland,WilliamC
DNA 聚合酶 γ (pol γ) 负责线粒体 DNA (mtDNA) 的复制和修复。在患有阿尔珀斯症、进行性外眼肌麻痹和共济失调神经病综合征等线粒体疾病的患者中，发现了超过 150 个 POLG（编码 pol γ）突变。然而，许多 POLG 疾病相关突变的严重程度和优势尚不清楚，因为它们在散发病例中已有报道。为了了解体内 pol γ 疾病相关突变的后果，我们鉴定了由 MIP1 基因保守区域的 31 个突变引起的 mtDNA 突变、耗竭和线粒体功能障碍的显性和隐性变化，MIP1 编码人类 pol γ 的酿酒酵母直系同源物。研究表明，二十种 mip1 突变酶会破坏 mtDNA 复制，并可能足以引起疾病。先前未表征的散发突变 Q308H、R807C、G1076V、R1096H 和 S1104C 导致聚合酶活性降低，导致 mtDNA 耗竭和线粒体功能障碍。我们提供的证据表明这些 POLG 突变的点突变在线粒体功能障碍和疾病进展中的作用有限。相反，大多数线粒体缺陷型 mip1 突变体表现出线粒体 DNA 减少或耗尽。我们还确定themip1突变株表型的严重程度与人类直系同源物相关疾病的发病年龄相关。最后，我们证明，通过核糖核苷酸还原酶（RNR1）的过表达来增加核苷酸库可以抑制由几个显性mip1突变引起的mtDNA复制缺陷，并且直系同源人类突变揭示了严重的核苷酸结合缺陷。
DNA polymerase γ (pol γ) is responsible for replication and repair of mitochondrial DNA (mtDNA). Over 150 mutations inPOLG(which encodes pol γ) have been discovered in patients with mitochondrial disorders including Alpers, progressive external ophthalmoplegia and ataxia-neuropathy syndrome. However, the severity and dominance of manyPOLGdisease-associated mutations are unclear, because they have been reported in sporadic cases. To understand the consequences of pol γ disease-associated mutationsin vivo, we identified dominant and recessive changes in mtDNA mutagenesis, depletion and mitochondrial dysfunction caused by 31 mutations in the conserved regions of the gene,MIP1, which encodes theSaccharomyces cerevisiaeortholog of human pol γ. Twentymip1mutant enzymes were shown to disrupt mtDNA replication and may be sufficient to cause disease. Previously uncharacterized sporadic mutations, Q308H, R807C, G1076V, R1096H and S1104C, caused decreased polymerase activity leading to mtDNA depletion and mitochondrial dysfunction. We present evidence showing a limited role of point mutagenesis by thesePOLGmutations in mitochondrial dysfunction and disease progression. Instead, most mitochondrial defectivemip1mutants displayed reduced or depleted mtDNA. We also determined that the severity of the phenotype of themip1mutant strain correlates with the age of onset of disease associated with the human ortholog. Finally, we demonstrated that increasing nucleotide pools by overexpression of ribonucleotide reductase (RNR1) suppressed mtDNA replication defects caused by several dominantmip1mutations, and the orthologous human mutations revealed severe nucleotide binding defects.
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影响因子：
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作者：
Bebenek,Katarzyna;Kunkel,ThomasA
通讯作者：
Kunkel,ThomasA
影响因子：
30.8
作者：
Vermulst, Marc;Bielas, Jason H.;Loeb, Lawrence A.
通讯作者：
Loeb, Lawrence A.
影响因子：
5
作者：
Lewis, William;Day, Brian J.;Copeland, William C.
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Copeland, William C.
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影响因子：
14.9
作者：
F. Sor;H. Fukuhara
通讯作者：
H. Fukuhara
真核 DNA 聚合酶的功能。
DOI：
--
发表时间：
2003
期刊：
Science of Aging Knowledge Environment
影响因子：
--
作者：
P. V. Shcherbakova;K. Bebenek;T. Kunkel
通讯作者：
T. Kunkel