Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators

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2015Suggested citation
Pijuan Marquilles, Jordi;
Marı́a, Carlos;
Herrero Perpiñán, Enrique;
Bellí i Martínez, Gemma;
.
(2015)
.
Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators.
Journal of Cell Science, 2015, vol. 128, p. 4653-4665.
https://doi.org/10.1242/jcs.178046.
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Show full item recordAbstract
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.