Free Radical Biology and Medicine 82 (2015) 73–104 Contents lists available at ScienceDirect Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed Review Article Mitochondria–nucleus network for genome stability Aneta Kaniak-Golik, Adrianna Skoneczna n Laboratory of Mutagenesis and DNA Repair, Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland article info abstract Article history: The proper functioning of the cell depends on preserving the cellular genome. In yeast cells, a limited Received 18 September 2014 number of genes are located on mitochondrial DNA. Although the mechanisms underlying nuclear Received in revised form genome maintenance are well understood, much less is known about the mechanisms that ensure 25 November 2014 mitochondrial genome stability. Mitochondria influence the stability of the nuclear genome and vice Accepted 13 January 2015 versa. Little is known about the two-way communication and mutual influence of the nuclear and Available online 30 January 2015 mitochondrial genomes. Although the mitochondrial genome replicates independent of the nuclear Keywords: genome and is organized by a distinct set of mitochondrial nucleoid proteins, nearly all genome stability Genome maintenance mechanisms responsible for maintaining the nuclear genome, such as mismatch repair, base excision 0 rho repair, and double-strand break repair via homologous recombination or the nonhomologous end- Oxidative stress joining pathway, also act to protect mitochondrial DNA. In addition to mitochondria-specificDNA Iron–sulfur cluster polymerase γ, the polymerases α, η, ζ, and Rev1 have been found in this organelle. A nuclear genome Heme protein Membrane potential instability phenotype results from a failure of various mitochondrial functions, such as an electron DNA damage transport chain activity breakdown leading to a decrease in ATP production, a reduction in the DNA repair mitochondrial membrane potential (ΔΨ), and a block in nucleotide and amino acid biosynthesis. The Protein assembly loss of ΔΨ inhibits the production of iron–sulfur prosthetic groups, which impairs the assembly of Fe–S Metal toxicity 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. & 2015 Elsevier Inc.. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents Introduction............................................................................................................. 74 Maintenance of the mitochondrial genome. 74 How is the ability to maintain stable mitochondrial DNA determined in S. cerevisiae cells?. 74 Mitochondrial nucleoid proteins in S. cerevisiae . 76 Replication of yeast mitochondrial DNA. 77 Other mitochondrial DNA polymerases . 78 Mitochondrial base excision repair (mtBER) . 79 Short-patch BER is mediated by monofunctional and bifunctional glycosylases . 79 Long-patch BER. 82 Mitochondrial mismatch repair and homologous recombination in mitochondria . 82 Msh1-dependent pathway . 82 Abbreviations: used: AP, apurinic/apyrimidinic, i.e., abasic; BER, base excision repair; DSB, DNA double-strand break; 50-dRP, 50-deoxyribose phosphate; CIA, cytosolic iron– sulfur protein assembly; DG, DNA glycosylase; DRM(D), direct repeat-mediated (deletion); ETC, electron transport chain; HR, homologous recombination; ISC, iron–sulfur cluster; LP BER, long-patch BER; MDR, multidrug resistance; MEPS, minimum efficiency processing segment; MMS, methyl methanesulfonate; NHEJ, nonhomologous end- joining pathway; 30-PUA, 30-phospho-α,β-unsaturated aldehyde; RCR, rolling-circle replication; RDR, recombination-dependent replication; ROS, reactive oxygen species; SP BER, short-patch BER; SSA, single-strand annealing; SSB, DNA single-strand break; TCA, tricarboxylic acid cycle, citric acid cycle, Krebs cycle; TLS, translesion synthesis; ΔΨ, mitochondrial membrane potential n Corresponding author. E-mail address: [email protected] (A. Skoneczna). http://dx.doi.org/10.1016/j.freeradbiomed.2015.01.013 0891-5849/& 2015 Elsevier Inc.. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 74 A. Kaniak-Golik, A. Skoneczna / Free Radical Biology and Medicine 82 (2015) 73–104 New findings on mitochondrial recombination pathways in yeast cells . 83 Degradation of mtDNA in the network of mtDNA maintenance pathways . 84 Mitochondrial influence on the nuclear genome. 84 Mutations that affect both the mitochondrial and the nuclear genomes . 84 Mutations that perturb the mitochondrial and nuclear genomes in various ways . 85 Mutations that impair mitochondrial functions are important for nuclear genome maintenance . 85 Altered function of the electron transport chain (ETC) can provoke nuclear genome instability . 85 Impaired iron–sulfur cluster production leads to nuclear genome rearrangements . 86 Abnormal dNTP pool size, altered bias, or changed cellular distribution often leads to mutagenesis and/or chromosomal instability . 87 Metal homeostasis disruption impairs prosthetic group creation to influence genome stability . 91 Detoxification and the stress response capacity of mitochondria prevent genotoxic stress and thereby help preserve the genome. 96 Apoptosis failure leads to genome instability . 98 Mitochondrial genome maintenance ensures functional mitochondria and contributes to nuclear genome stability. 99 Conclusions.............................................................................................................99 Acknowledgments. 99 References..............................................................................................................99 Introduction Maintenance of the mitochondrial genome Mitochondria are double-membrane-bound organelles that are α How is the ability to maintain stable mitochondrial DNA determined thought to have evolved from endosymbiotic -proteobacteria and in S. cerevisiae cells? that are essential for the viability of eukaryotic cells. Mitochondria perform a variety of functions: produce bulk cellular ATP through the Before describing the mtDNA maintenance pathways that function energy conversion reactions of oxidative phosphorylation and the in yeast cells, we will introduce a few terms that are specificto tricarboxylic acid cycle; maintain and express the residual mitochon- S. cerevisiae mitochondrial genetics and describe the nonrespiratory drial genome that is required for oxidative phosphorylation; perform reporter gene that was engineered into the yeast mitochondrial important steps of heme biosynthesis, amino acid biosynthesis, genome and shown to be a useful tool for assaying mtDNA stability nucleotide biosynthesis, the urea cycle, and fatty acid metabolism; in this organism. Because S. cerevisiae cells remain viable upon the þ and participate in apoptosis and reactive oxygen species production. loss of functional mtDNA, known as the rho mitochondrial genome, the so-called cytoplasmic petite mutants, i.e., nonrespiring clones that Mitoproteomics studies have indicated that there are ca. 1000 form minute colonies on standard glucose-limited medium, can be mitochondrial proteins in cells of the yeast Saccharomyces cerevisiae isolated easily (reviewed in [13]). These mutants arise from either [1,2] and ca. 1500 proteins in human mitochondria [3].Onlyasmall extensive deletions of mtDNA followed by reamplification of the fraction of these proteins is encoded by mitochondrial genomes, and remaining fragment (rhoÀ genomes/mutants) or a complete loss of this group primarily includes proteins involved in oxidative phos- mtDNA (rho0 mutants). Therefore, at least three rho genotypes are phorylation and ATP synthesis (8 proteins in yeast mitochondria and possible: rhoþ (wild-type), rhoÀ (partial deletion of the mitochondrial 13 proteins in human mitochondria, because yeast mitochondria lack genome), and rho0 (complete loss of mtDNA). subunits of the respiratory chain complex I that are present in human Although rhoÀ and rho0 petites are phenotypically identical, they mitochondria), as well as rRNA and tRNA genes that are required for probably originate from fundamentally different mechanisms. mitochondrial gene expression. Consequently, the vast majority of Petites with no mtDNA are often produced by a failure to transmit À mitochondrial proteins are encoded by the nuclear genome, synthe- mtDNA to the progeny, whereas rho petites most likely result from sized on cytosolic ribosomes and imported into the mitochondria recombination events that form partially deleted and rearranged mtDNA molecules (reviewed in [13,14]). The petite mutations are [4,5]. None of the mitochondrial functions listed above are essential markedly pleiotropic because the mutants are unable to perform for the viability of S. cerevisiae cells, yet protein import into mitochon- mitochondrial protein synthesis (essential components of the dria is essential [4], highlighting the importance of this cellular mitochondrial translation apparatus are encoded by mtDNA, see compartment. One of the recently recognized