p53 in mitochondria enhances the accuracy of DNA synthesis
p53 in mitochondria enhances the accuracy of DNA synthesis
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DOI：
10.1038/cdd.2008.122
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发表时间：
2008-12-01
影响因子：
12.4
通讯作者：
Rahav, G.
中科院分区：
文献类型：
--
作者：
Bakhanashvili, M.;Grinberg, S.;Rahav, G.
p53在应激和非应激细胞中的线粒体定位。p53参与DNA修复和凋亡。它与线粒体DNA和DNA聚合酶γ（pol γ）发挥物理和功能相互作用。在p53缺失的H1299细胞的线粒体部分中检查了DNA合成期间p53和pol γ的功能合作，作为pol γ的来源。结果表明，p53可能影响线粒体DNA合成的准确性：（1）在（a）重组野生型p53（wtp 53）;（B）表达内源性wtp 53的LCC 2细胞胞质组分存在下，（但不是特异性的预耗尽级分）;（c）过表达wtp 53但不表达核酸外切酶缺陷型突变体p53-R175 H的H1299细胞的细胞质提取物。(2)HCT 116（p53 +/+）细胞的线粒体提取物显示出比HCT 116（p53-/-）细胞更高的核酸外切酶活性。外源性p53的添加补充了HCT 116（p53-/-）线粒体提取物错配切除。此外，与HCT 116（p53-/-）细胞相比，HCT 116（p53 +/+）细胞线粒体部分的错误掺入较低。(3)辐射诱导的HCT 116（p53 +/+）细胞中内源性p53的线粒体易位与纠错活性的增强相关。总之，这些数据表明，线粒体中的p53可能是错误修复途径的一个组成部分，并作为线粒体基因组的监护人。并对p53在DNA修复和细胞凋亡中的作用进行了讨论。
Mitochondrial localization of p53 was observed in stressed and unstressed cells. p53 is involved in DNA repair and apoptosis. It exerts physical and functional interactions with mitochondrial DNA and DNA polymerase gamma (pol gamma). The functional cooperation of p53 and pol gamma during DNA synthesis was examined in the mitochondrial fraction of p53-null H1299 cells, as the source of pol gamma. The results show that p53 may affect the accuracy of DNA synthesis in mitochondria: (1) the excision of a misincorporated nucleotide increases in the presence of (a) recombinant wild-type p53 (wtp53); (b) cytoplasmic fraction of LCC2 cells expressing endogenous wtp53 (but not specifically pre-depleted fraction); (c) cytoplasmic extract of H1299 cells overexpressing wtp53, but not exonuclease-deficient mutant p53-R175H. (2) Mitochondrial extracts of HCT116(p53 +/+) cells display higher exonuclease activity compared with that of HCT116(p53-/-) cells. Addition of exogenous p53 complements the HCT116(p53-/-) mitochondrial extract mispair excision. Furthermore, the misincorporation was lower in the mitochondrial fraction of HCT116(p53 +/+) cells as compared with that of HCT116(p53 -/-) cells. (3) Irradiation-induced mitochondrial translocation of endogenous p53 in HCT116(p53 +/+) cells correlates with the enhancement of error-correction activities. Taken together, the data suggest that p53 in mitochondria may be a component of an error-repair pathway and serve as guardian of the mitochondrial genome. The function of p53 in DNA repair and apoptosis is discussed.