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

Pijuan Marquilles, Jordi; Marı́a, Carlos; Herrero Perpiñán, Enrique; Bellí i Martínez, Gemma

doi:https://doi.org/10.1242/jcs.178046

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Issue date

2015

Author

Pijuan Marquilles, Jordi

Marı́a, Carlos

Herrero Perpiñán, Enrique

Bellí i Martínez, Gemma

Suggested 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.

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.

URI

http://hdl.handle.net/10459.1/58928

DOI

https://doi.org/10.1242/jcs.178046

Is part of

Journal of Cell Science, 2015, vol. 128, p. 4653-4665