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 postreplication repair and the homologous recombination pathways, demonstrating that a DNA damage response needs to be activated upon ISC impairment to preserve cell viability.

BRCA 1 and BARD 1 mediate apoptotic resistance but not longevity upon mitochondrial stress in Caenorhabditis elegans

“…As an alternative to DNA damage, DDR could be induced by changes in chromatin structure [51], which have been also implicated in mitochondrial stress control of longevity [30,52]. Furthermore, in yeast, mitochondrial dysfunction leads to DDR activation via defective iron-sulfur cluster (ISC) biogenesis [53,54]. Different DNA repair genes which we found to mediate isp-1 mutants phenotypes (e.g., DNA-glycosylases, helicases, nucleases [55][56][57]) rely on ISC, whose biogenesis is impaired by frataxin depletion [58,59] and could be similarly affected upon suppression of ISP-1, an ISC protein itself.…”

Yeast Dun1 Kinase Regulates Ribonucleotide Reductase Small Subunit Localization in Response to Iron Deficiency

“…Consistent with those results, a recent study has shown that cells lacking Grx5 glutaredoxin, another member of the core mitochondrial ISC synthesis pathway, promote Sml1 protein degradation through a Dun1-dependent but Mec1/Rad53-independent mechanism (59). However, cells lacking non-core ISC member Iba57, which functions in transferring 4Fe-4S clusters to mitochondrial targets (60,61), or cells in which expression of Npb35, an essential component of cytoplasmic iron-sulfur cluster assembly machinery (62), has been repressed, induce Sml1 protein degradation through a mechanism that requires both Dun1 and Mec1 kinase proteins (59). Given that iron deficiency leads to down-regulation of the ISC synthesis pathway, we propose that various signaling pathways modulate Dun1 kinase function through its FHA domain or Thr-380 residue in response to iron limitation.…”

Expression of mammalian Onzin and Fungal Cadmium Resistance 1 in S. cerevisiae suggests ancestral functions of PLAC8 proteins in regulating mitochondrial metabolism and DNA damage repair

“…The nuclear DNA damage caused by defects of ISC biosynthesis activates at least two different signalling pathways that converge at Dun1p, a protein kinase that controls the DNA damage response in yeast [61]. The DNA damage checkpoint mediated by the Mec1p–Chk1p– Dun1p signaling transduction pathway was found to be activated by dysfunctions in ISC-targeting factors, which are not required for the biogenesis of ISC but act specifically for transferring ISC to mitochondrial target apoproteins [62]. By contrast, dysfunctions of the core mitochondrial ISC assembly machinery induced a second pathway involving a Mec1p-independent activation of Dun1p.…”