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-ca
• dc.contributor.author Domènech, Albaca
• dc.contributor.author Carmona, Mercèca
• dc.contributor.author García Santamarina, Sarela, 1978-ca
• dc.contributor.author Bañó, M. Carmenca
• dc.contributor.author Ayté del Olmo, Joséca
• dc.contributor.author Hidalgo Hernando, Elenaca
• dc.date.accessioned 2017-07-11T07:39:00Z
• dc.date.available 2017-07-11T07:39:00Z
• dc.date.issued 2017
• 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/pdfca
• 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.doi http://dx.doi.org/10.1371/journal.pgen.1006858
• dc.identifier.issn 1553-7390
• dc.identifier.uri http://hdl.handle.net/10230/32525
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)ca
• dc.relation.ispartof PLoS Genetics. 2017;13(6):e1006858
• 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 © 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.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• 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.title Lack of a peroxiredoxin suppresses the lethality of cells devoid of electron donors by channelling electrons to oxidized ribonucleotide reductaseca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion