title: DNA replication inhibitor hydroxyurea alters Fe-S centers by producing reactive oxygen species in vivo.
abstract: Redox homeostasis is tightly controlled in cells as it is critical for most cellular functions. Iron-Sulfur centers (Fe-S) are metallic cofactors with electronic properties that are associated with proteins and allow fine redox tuning. Following the observation that altered Fe-S biosynthesis is correlated with a high sensitivity to hydroxyurea (HU), a potent DNA replication blocking agent, we identified that oxidative stress response pathway under the control of the main regulator Yap1 attenuates HU deleterious effects, as it significantly increases resistance to HU, Fe-S biosynthesis and DNA replication kinetics in the presence of HU. Yap1 effect is mediated at least in part through up-regulation of two highly conserved genes controlling cytosolic Fe-S biosynthesis and oxidative stress, Dre2 and Tah18. We next observed that HU produces deleterious effects on cytosolic Fe-S clusters in proteins in vivo but not in vitro, suggesting that HU's impact on Fe-S in vivo is mediated by cellular metabolism. Finally, we evidenced that HU exposure was accompanied by production of reactive oxygen species intracellularly. Altogether, this study provides mechanistic insight on the initial observation that mutants with altered Fe-S biosynthesis are highly sensitive to HU and uncovers a novel mechanism of action of this widely used DNA replication inhibitor.
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3348, 91405 Orsay, France.|Institut Curie, CNRS UMR2027, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, CNRS UMR3348, 91405 Orsay, France.
authors.forename: Meng-Er
authors.initials: ME
authors.lastname: Huang
authors.affiliation: Institut Curie, CNRS UMR2027, 91405 Orsay, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Facca
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3348, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, CNRS UMR3348, 91405 Orsay, France.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Fatmi
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3348, 91405 Orsay, France.|Institut Curie, CNRS UMR2027, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, CNRS UMR3348, 91405 Orsay, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Baïlle
authors.affiliation: Institut Curie, CNRS UMR2027, 91405 Orsay, France.
authors.forename: Safia
authors.initials: S
authors.lastname: Bénakli
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR3348, 91405 Orsay, France.|Institut Curie, CNRS UMR2027, 91405 Orsay, France.|Université Paris Sud, Université Paris-Saclay, CNRS UMR3348, 91405 Orsay, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Vernis
mesh_terms: D004261:DNA Replication / Q000187:drug effects*; D004271:DNA, Fungal / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006918:Hydroxyurea / Q000494:pharmacology*; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004271:DNA, Fungal; D007506:Iron-Sulfur Proteins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; D006918:Hydroxyurea