Activation of Dun1 in response to nuclear DNA instability accounts for the increase in mitochondrial point mutations in Rad27/FEN1 deficient S. cerevisiae
| Autor: | Renata Kuberska, Ewa Sledziewska-Gojska, Piotr Dzierzbicki, Aneta Kaniak-Golik |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Flap Endonucleases Gene Identification and Analysis lcsh:Medicine Cell Cycle Proteins Genetic Networks Mitochondrion medicine.disease_cause Biochemistry Gene Knockout Techniques Antibiotics Medicine and Health Sciences DNA Fungal Homologous Recombination lcsh:Science Energy-Producing Organelles Mutation Multidisciplinary Antimicrobials Chemistry Drugs Mitochondrial DNA Mitochondria Erythromycin Nuclear DNA Nucleic acids Cellular Structures and Organelles Network Analysis Research Article Computer and Information Sciences Saccharomyces cerevisiae Proteins Forms of DNA DNA recombination DNA damage Saccharomyces cerevisiae Protein Serine-Threonine Kinases Bioenergetics DNA Mitochondrial Microbiology Genomic Instability 03 medical and health sciences Acetyltransferases Microbial Control Genetics medicine Point Mutation Cell Nucleus Pharmacology Point mutation lcsh:R Membrane Proteins Biology and Life Sciences Cell Biology DNA G2-M DNA damage checkpoint Molecular biology Enzyme Activation 030104 developmental biology Mutagenesis lcsh:Q Homologous recombination DNA Damage |
| Zdroj: | PLoS ONE, Vol 12, Iss 7, p e0180153 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0180153 |
| Popis: | Rad27/FEN1 nuclease that plays important roles in the maintenance of DNA stability in the nucleus has recently been shown to reside in mitochondria. Accordingly, it has been established that Rad27 deficiency causes increased mutagenesis, but decreased microsatellite instability and homologous recombination in mitochondria. Our current analysis of mutations leading to erythromycin resistance indicates that only some of them arise in mitochondrial DNA and that the GC→AT transition is a hallmark of the mitochondrial mutagenesis in rad27 null background. We also show that the mitochondrial mutator phenotype resulting from Rad27 deficiency entirely depends on the DNA damage checkpoint kinase Dun1. DUN1 inactivation suppresses the mitochondrial mutator phenotype caused by Rad27 deficiency and this suppression is eliminated at least in part by subsequent deletion of SML1 encoding a repressor of ribonucleotide reductase. We conclude that Rad27 deficiency causes a mitochondrial mutator phenotype via activation of DNA damage checkpoint kinase Dun1 and that a Dun1-mediated increase of dNTP pools contributes to this phenomenon. These results point to the nuclear DNA instability as the source of mitochondrial mutagenesis. Consistently, we show that mitochondrial mutations occurring more frequently in yeast devoid of Rrm3, a DNA helicase involved in rDNA replication, are also dependent on Dun1. In addition, we have established that overproduction of Exo1, which suppresses DNA damage sensitivity and replication stress in nuclei of Rad27 deficient cells, but does not enter mitochondria, suppresses the mitochondrial mutagenesis. Exo1 overproduction restores also a great part of allelic recombination and microsatellite instability in mitochondria of Rad27 deficient cells. In contrast, the overproduction of Exo1 does not influence mitochondrial direct-repeat mediated deletions in rad27 null background, pointing to this homologous recombination pathway as the direct target of Rad27 activity in mitochondria. |
| Databáze: | OpenAIRE |
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