Kaniak-Golik Aneta, Skoneczna Adrianna
Laboratory of Mutagenesis and DNA Repair, Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland.
Laboratory of Mutagenesis and DNA Repair, Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland.
Free Radic Biol Med. 2015 May;82:73-104. doi: 10.1016/j.freeradbiomed.2015.01.013. Epub 2015 Jan 30.
The proper functioning of the cell depends on preserving the cellular genome. In yeast cells, a limited number of genes are located on mitochondrial DNA. Although the mechanisms underlying nuclear genome maintenance are well understood, much less is known about the mechanisms that ensure mitochondrial genome stability. Mitochondria influence the stability of the nuclear genome and vice versa. Little is known about the two-way communication and mutual influence of the nuclear and mitochondrial genomes. Although the mitochondrial genome replicates independent of the nuclear genome and is organized by a distinct set of mitochondrial nucleoid proteins, nearly all genome stability mechanisms responsible for maintaining the nuclear genome, such as mismatch repair, base excision repair, and double-strand break repair via homologous recombination or the nonhomologous end-joining pathway, also act to protect mitochondrial DNA. In addition to mitochondria-specific DNA polymerase γ, the polymerases α, η, ζ, and Rev1 have been found in this organelle. A nuclear genome instability phenotype results from a failure of various mitochondrial functions, such as an electron transport chain activity breakdown leading to a decrease in ATP production, a reduction in the mitochondrial membrane potential (ΔΨ), and a block in nucleotide and amino acid biosynthesis. The loss of ΔΨ inhibits the production of iron-sulfur prosthetic groups, which impairs the assembly of Fe-S proteins, including those that mediate DNA transactions; disturbs iron homeostasis; leads to oxidative stress; and perturbs wobble tRNA modification and ribosome assembly, thereby affecting translation and leading to proteotoxic stress. In this review, we present the current knowledge of the mechanisms that govern mitochondrial genome maintenance and demonstrate ways in which the impairment of mitochondrial function can affect nuclear genome stability.
细胞的正常功能依赖于对细胞基因组的保护。在酵母细胞中，线粒体DNA上仅含有有限数量的基因。虽然核基因组维持的潜在机制已得到充分了解，但对于确保线粒体基因组稳定性的机制却知之甚少。线粒体影响核基因组的稳定性，反之亦然。关于核基因组与线粒体基因组之间的双向通讯和相互影响，人们了解得很少。尽管线粒体基因组独立于核基因组进行复制，并由一组独特的线粒体类核蛋白组织，但几乎所有负责维持核基因组的基因组稳定性机制，如错配修复、碱基切除修复以及通过同源重组或非同源末端连接途径进行的双链断裂修复，也都作用于保护线粒体DNA。除了线粒体特异性DNA聚合酶γ外，还在该细胞器中发现了聚合酶α、η、ζ和Rev1。各种线粒体功能的缺陷会导致核基因组不稳定表型，例如电子传递链活性崩溃导致ATP生成减少、线粒体膜电位（ΔΨ）降低以及核苷酸和氨基酸生物合成受阻。ΔΨ的丧失会抑制铁硫辅基的产生，这会损害包括介导DNA交易的那些蛋白在内的铁硫蛋白的组装；扰乱铁稳态；导致氧化应激；并干扰摆动tRNA修饰和核糖体组装，从而影响翻译并导致蛋白毒性应激。在本综述中，我们介绍了目前关于线粒体基因组维持机制的知识，并展示了线粒体功能受损影响核基因组稳定性的方式。
