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 defects at different stages of the mitochondrial Fe-S cluster assembly machinery (ISC) result in increased spontaneous mutation rate and hyperrecombination, 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 Rnr2/4 enzyme subunits. Depending on the impaired stage of the ISC machinery, different signaling pathway mediators contribute to such response, converging in Dun1. Thus, cells lacking Grx5 glutaredoxin, which are compromised at the core ISC system, show Mec1/Rad53-independent Dun1 activation, whereas both Mec1 and Chk1 are required when the non-core ISC member Iba57 is absent. Grx5-less cells exhibit a strong dependence on the error-free post-replication repair and the homologous recombination pathways, demonstrating that a DNA damage response is required to be activated upon ISC impairment to preserve cell viability.