Pir1p Mediates Translocation of the Yeast Apn1p Endonuclease into the Mitochondria To Maintain Genomic Stability
Pir1p Mediates Translocation of the Yeast Apn1p Endonuclease into the Mitochondria To Maintain Genomic Stability
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Pir1p 介导酵母 Apn1p 核酸内切酶易位至线粒体以维持基因组稳定性
DOI：
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发表时间：
2001
影响因子：
5.3
通讯作者：
D. Ramotar
中科院分区：
文献类型：
--
作者：
R. Vongsamphanh;Pierre;D. Ramotar
摘要线粒体基因组不断受到有氧代谢产生的活性氧的攻击。这会导致各种高度遗传毒性的DNA损伤的形成，包括基本部位。酵母Apn1p定位于细胞核，在那里它具有切割碱性位点的功能，而Apn1Δ突变体对诱导碱性位点的药物如甲磺酸甲酯高度敏感。在这里，我们首次证明了酵母Apn1p也定位于线粒体。我们发现Pir1p最初是作为未知功能的细胞壁成分分离出来的，它与Apn1p的C末端相互作用，后者携带两部分核定位信号。进一步的分析表明，Pir1p是导致Apn1p线粒体定位所必需的，可能是通过与核运输机制竞争来实现的。Pir1Δ突变体显示出细胞核内Apn1p的显著增加(∼3倍)，这与线粒体中Apn1p水平的急剧下降相一致。为了探讨Apn1p-Pir1p相互作用的功能后果，我们测量了野生型和Pir1Δ和Apn1Δ突变体的线粒体突变率。暴露于MMS的Pir1Δ和Apn1Δ突变体的线粒体突变率分别增加了3.6%和5.8%，强调了Apn1p在线粒体基因组修复中的重要性。我们得出结论，Pir1p与Apn1p在细胞质或核水平上相互作用，并促进Apn1p转运到线粒体以修复受损的DNA。
ABSTRACT The mitochondrial genome is continuously subject to attack by reactive oxygen species generated through aerobic metabolism. This leads to the formation of a variety of highly genotoxic DNA lesions, including abasic sites. Yeast Apn1p is localized to the nucleus, where it functions to cleave abasic sites, and apn1 Δ mutants are hypersensitive to agents such as methyl methanesulfonate (MMS) that induce abasic sites. Here we demonstrate for the first time that yeast Apn1p is also localized to the mitochondria. We found that Pir1p, initially isolated as a cell wall constituent of unknown function, interacts with the C-terminal end of Apn1p, which bears a bipartite nuclear localization signal. Further analysis revealed that Pir1p is required to cause Apn1p mitochondrial localization, presumably by competing with the nuclear transport machinery. pir1Δ mutants displayed a striking (∼3-fold) increase of Apn1p in the nucleus, which coincided with drastically reduced levels in the mitochondria. To explore the functional consequences of the Apn1p-Pir1p interaction, we measured the rate of mitochondrial mutations in the wild type and pir1Δ and apn1Δ mutants.pir1Δ and apn1Δ mutants exposed to MMS exhibited 3.6- and 5.8-fold increases, respectively, in the rate of mitochondrial mutations, underscoring the importance of Apn1p in repair of the mitochondrial genome. We conclude that Pir1p interacts with Apn1p, at the level of either the cytoplasm or nucleus, and facilitates Apn1p transport into the mitochondria to repair damaged DNA.
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DOI：
10.1073/pnas.97.1.250
发表时间：
2000-01
影响因子：
11.1
作者：
E. Sia;Christine A. Butler;M. Dominska;P. Greenwell;T. Fox;T. Petes
通讯作者：
E. Sia;Christine A. Butler;M. Dominska;P. Greenwell;T. Fox;T. Petes
影响因子：
14.9
作者：
Grishko, VI;Druzhyna, N;Wilson, GL
通讯作者：
Wilson, GL
影响因子：
3.3
作者：
P. James;J. Halladay;E. Craig
通讯作者：
P. James;J. Halladay;E. Craig
DOI：
10.1016/s0021-9258(19)81317-0
发表时间：
1988-12
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Arlen W. Johnson;B. Demple
通讯作者：
Arlen W. Johnson;B. Demple
酿酒酵母拥有大肠杆菌核酸内切酶 III 的两种功能同源物。
DOI：
10.1021/bi973042h
发表时间：
1998
期刊：
Biochemistry.
影响因子：
--
作者：
You,HJ;Swanson,RL;Doetsch,PW
通讯作者：
Doetsch,PW