title: Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators.
abstract: Fe-S cluster biogenesis machinery is required for multiple DNA metabolism processes. In this work, we show that, in Saccharomyces cerevisiae, defects at different stages of the mitochondrial Fe-S cluster assembly machinery (ISC) result in increased spontaneous mutation rate and hyper-recombination, accompanied by an increment in Rad52-associated DNA repair foci and a higher phosphorylated state of γH2A histone, altogether supporting the presence of constitutive DNA lesions. Furthermore, ISC assembly machinery deficiency elicits a DNA damage response that upregulates ribonucleotide reductase activity by promoting the reduction of Sml1 levels and the cytosolic redistribution of Rnr2 and Rnr4 enzyme subunits. Depending on the impaired stage of the ISC machinery, different signaling pathway mediators contribute to such a response, converging on Dun1. Thus, cells lacking the glutaredoxin Grx5, which are compromised at the core ISC system, show Mec1- and Rad53-independent Dun1 activation, whereas both Mec1 and Chk1 are required when the non-core ISC member Iba57 is absent. Grx5-null cells exhibit a strong dependence on the error-free post-replication repair and the homologous recombination pathways, demonstrating that a DNA damage response needs to be activated upon ISC impairment to preserve cell viability.
authors.affiliation: Department of Basic Medical Sciences, IRBLleida, University of Lleida, Lleida 25198, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Pijuan
authors.affiliation: Department of Basic Medical Sciences, IRBLleida, University of Lleida, Lleida 25198, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: María
authors.affiliation: Department of Basic Medical Sciences, IRBLleida, University of Lleida, Lleida 25198, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Herrero
authors.affiliation: Department of Basic Medical Sciences, IRBLleida, University of Lleida, Lleida 25198, Spain gemma.belli@cmb.udl.cat.
authors.forename: Gemma
authors.initials: G
authors.lastname: Bellí
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D054477:Glutaredoxins; C528773:Grx5 protein, S cerevisiae; C527305:Iba57 protein, S cerevisiae; D047908:Intracellular Signaling Peptides and Proteins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; C497197:RAD52 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; C115052:SML1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C570014:RNR2 protein, S cerevisiae; D012264:Ribonucleotide Reductases; D011494:Protein Kinases; C104169:DUN1 protein, S cerevisiae; D000071877:Checkpoint Kinase 1; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases
keywords: DNA damage response checkpoint; Fe-S cluster biogenesis; Glutaredoxin; Post-replication repair; Ribonucleotide reductase