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Lack of a peroxiredoxin suppresses the lethality of cells devoid of electron donors by channelling electrons to oxidized ribonucleotide reductase

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dc.contributor.author Boronat i Llop, Susanna, 1965-
dc.contributor.author Domènech, Alba
dc.contributor.author Carmona, Mercè
dc.contributor.author García Santamarina, Sarela, 1978-
dc.contributor.author Bañó, M. Carmen
dc.contributor.author Ayté del Olmo, José
dc.contributor.author Hidalgo Hernando, Elena
dc.date.accessioned 2017-07-11T07:39:00Z
dc.date.available 2017-07-11T07:39:00Z
dc.date.issued 2017
dc.identifier.citation Boronal S, Domènech A, Carmona M, García-Santamarina S, Bañó MC, Ayté J, Hidalgo E. Lack of a peroxiredoxin suppresses the lethality of cells devoid of electron donors by channelling electrons to oxidized ribonucleotide reductase. PLoS Genetics. 2017;13(6):e1006858. DOI: 10.1371/journal.pgen.1006858
dc.identifier.issn 1553-7390
dc.identifier.uri http://hdl.handle.net/10230/32525
dc.description.abstract The thioredoxin and glutaredoxin pathways are responsible of recycling several enzymes which undergo intramolecular disulfide bond formation as part of their catalytic cycles such as the peroxide scavengers peroxiredoxins or the enzyme ribonucleotide reductase (RNR). RNR, the rate-limiting enzyme of deoxyribonucleotide synthesis, is an essential enzyme relying on these electron flow cascades for recycling. RNR is tightly regulated in a cell cycle-dependent manner at different levels, but little is known about the participation of electron donors in such regulation. Here, we show that cytosolic thioredoxins Trx1 and Trx3 are the primary electron donors for RNR in fission yeast. Unexpectedly, trx1 transcript and Trx1 protein levels are up-regulated in a G1-to-S phase-dependent manner, indicating that the supply of electron donors is also cell cycle-regulated. Indeed, genetic depletion of thioredoxins triggers a DNA replication checkpoint ruled by Rad3 and Cds1, with the final goal of up-regulating transcription of S phase genes and constitutive RNR synthesis. Regarding the thioredoxin and glutaredoxin cascades, one combination of gene deletions is synthetic lethal in fission yeast: cells lacking both thioredoxin reductase and cytosolic dithiol glutaredoxin. We have isolated a suppressor of this lethal phenotype: a mutation at the Tpx1-coding gene, leading to a frame shift and a loss-of-function of Tpx1, the main client of electron donors. We propose that in a mutant strain compromised in reducing equivalents, the absence of an abundant and competitive substrate such as the peroxiredoxin Tpx1 has been selected as a lethality suppressor to favor RNR function at the expense of the non-essential peroxide scavenging function, to allow DNA synthesis and cell growth.
dc.description.sponsorship This work was supported by the Ministerio de Economía y Competitividad (Spain), PLAN E and FEDER (BFU2015-68350-P to EH, BFU2015-66347-P to JA, BFU2014-58429-P to MCB), and by 2014-SGR-154 from Generalitat de Catalunya (Spain) to EH and JA. AD is recipient of a pre-doctoral fellowship from Generalitat de Catalunya (Spain). EH is recipient of an ICREA Academia Award (Generalitat de Catalunya, Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartof PLoS Genetics. 2017;13(6):e1006858
dc.rights © 2017 Boronat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.title Lack of a peroxiredoxin suppresses the lethality of cells devoid of electron donors by channelling electrons to oxidized ribonucleotide reductase
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1006858
dc.subject.keyword Electron donors
dc.subject.keyword Synthesis phase
dc.subject.keyword Schizosaccharomyces pombe
dc.subject.keyword DNA replication
dc.subject.keyword Cell cycle and cell division
dc.subject.keyword Oxidation
dc.subject.keyword DNA transcription
dc.subject.keyword Peroxides
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-66347-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-58429-P
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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