title: Zim17/Tim15 links mitochondrial iron-sulfur cluster biosynthesis to nuclear genome stability.
abstract: Genomic instability is related to a wide-range of human diseases. Here, we show that mitochondrial iron-sulfur cluster biosynthesis is important for the maintenance of nuclear genome stability in Saccharomyces cerevisiae. Cells lacking the mitochondrial chaperone Zim17 (Tim15/Hep1), a component of the iron-sulfur biosynthesis machinery, have limited respiration activity, mimic the metabolic response to iron starvation and suffer a dramatic increase in nuclear genome recombination. Increased oxidative damage or deficient DNA repair do not account for the observed genomic hyperrecombination. Impaired cell-cycle progression and genetic interactions of ZIM17 with components of the RFC-like complex involved in mitotic checkpoints indicate that replicative stress causes hyperrecombination in zim17Δ mutants. Furthermore, nuclear accumulation of pre-ribosomal particles in zim17Δ mutants reinforces the importance of iron-sulfur clusters in normal ribosome biosynthesis. We propose that compromised ribosome biosynthesis and cell-cycle progression are interconnected, together contributing to replicative stress and nuclear genome instability in zim17Δ mutants.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC, Avd Américo Vespucio, 41092 Sevilla, Spain.
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: Díaz de la Loza
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gallardo
authors.forename: María Luisa
authors.initials: ML
authors.lastname: García-Rubio
authors.forename: Alicia
authors.initials: A
authors.lastname: Izquierdo
authors.forename: Enrique
authors.initials: E
authors.lastname: Herrero
authors.forename: Andrés
authors.initials: A
authors.lastname: Aguilera
authors.forename: Ralf Erik
authors.initials: RE
authors.lastname: Wellinger
mesh_terms: D002467:Cell Nucleus / Q000235:genetics*; D004249:DNA Damage; D004261:DNA Replication; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D042822:Genomic Instability; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000096:biosynthesis*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D045522:Recombinases / Q000378:metabolism; D011995:Recombination, Genetic; D051818:Replication Protein C / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D016196:S Phase; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D045522:Recombinases; D029701:Saccharomyces cerevisiae Proteins; C495990:Zim17 protein, S cerevisiae; D007501:Iron; D051818:Replication Protein C