Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane
Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane
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DOI：
10.1096/fj.09-147991
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发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Bohr, Vilhelm A.
中科院分区：
文献类型：
--
作者：
Aamann, Maria D.;Sorensen, Martin M.;Bohr, Vilhelm A.
科凯恩综合征 (CS) 是一种与严重发育缺陷和神经退行性疾病相关的人类过早衰老疾病，其表型类似于一些线粒体 DNA (mtDNA) 疾病。大多数患者属于互补B组，CS B组（CSB）蛋白在基因组维护和转录组调控中发挥作用。通过免疫细胞化学、线粒体分级分离和蛋白质印迹，我们证明 CSB 定位于不同类型细胞的线粒体，在甲萘醌诱导的氧化应激后线粒体分布增加。此外，我们的结果表明 CSB 在线粒体碱基切除修复（BER）调节中发挥着重要作用。特别是，我们发现与野生型细胞相比，CSB 缺陷细胞中 8-氧代-鸟嘌呤、尿嘧啶和 5-羟基尿嘧啶 BER 切口活性降低。这种缺陷与 BER 活性与线粒体内膜的关联不足相关，表明 CSB 可能参与 DNA 修复复合物的锚定。 CSB 缺陷细胞的 mtDNA 突变频率增加表明线粒体中存在 CSB 的功能意义。总体结果表明，CSB 通过帮助招募、稳定和/或保留与线粒体内膜相关的修复复合物中的 BER 蛋白，在线粒体 BER 中发挥直接作用，这或许为理解这种衰弱性疾病的复杂表型提供了新的基础。-Aamann, M. D.、Sorensen, M. M.、Hvitby, C.、Berquist, B. R.、Muftuoglu, M., Tian, J., de Souza-Pinto, N. C., Scheibye-Knudsen, M., Wilson, D. M., III, Stevnsner, T., Bohr, V. A. Cockayne 综合征 B 组蛋白通过支持与线粒体膜的 DNA 修复关联来促进线粒体 DNA 稳定性。 FASEB J. 24, 2334-2346 (2010)。 www.fasebj.org
Cockayne syndrome (CS) is a human premature aging disorder associated with severe developmental deficiencies and neurodegeneration, and phenotypically it resembles some mitochondrial DNA (mtDNA) diseases. Most patients belong to complementation group B, and the CS group B (CSB) protein plays a role in genomic maintenance and transcriptome regulation. By immunocytochemistry, mitochondrial fractionation, and Western blotting, we demonstrate that CSB localizes to mitochondria in different types of cells, with increased mitochondrial distribution following menadione-induced oxidative stress. Moreover, our results suggest that CSB plays a significant role in mitochondrial base excision repair (BER) regulation. In particular, we find reduced 8-oxo-guanine, uracil, and 5-hydroxy-uracil BER incision activities in CSB-deficient cells compared to wild-type cells. This deficiency correlates with deficient association of the BER activities with the mitochondrial inner membrane, suggesting that CSB may participate in the anchoring of the DNA repair complex. Increased mutation frequency in mtDNA of CSB-deficient cells demonstrates functional significance of the presence of CSB in the mitochondria. The results in total suggest that CSB plays a direct role in mitochondrial BER by helping recruit, stabilize, and/or retain BER proteins in repair complexes associated with the inner mitochondrial membrane, perhaps providing a novel basis for understanding the complex phenotype of this debilitating disorder.-Aamann, M. D., Sorensen, M. M., Hvitby, C., Berquist, B. R., Muftuoglu, M., Tian, J., de Souza-Pinto, N. C., Scheibye-Knudsen, M., Wilson, D. M., III, Stevnsner, T., Bohr, V. A. Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane. FASEB J. 24, 2334-2346 (2010). www.fasebj.org