The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2

In response to hydrogen peroxide (H2O2), the transcription factor Pap1 from Schizosaccharomyces pombe regulates transcription of genes required for adaptation to oxidative stress and for tolerance to toxic drugs. H2O2 induces oxidation of Pap1, its nuclear accumulation and expression of more than fifty Pap1-dependent genes. Oxidation and nuclear accumulation of Pap1 can also be accomplished by genetic inhibition of thioredoxin reductase. Furthermore, genetic alteration of the nuclear export pathway, or mutations in Pap1 nuclear export signal trigger nuclear accumulation of reduced Pap1. We show here that a subset of Pap1-dependent genes, such as those coding for the efflux pump Caf5, the ubiquitin-like protein Obr1 or the dehydrogenase SPCC663.08c, only require nuclear Pap1 for activation, whereas another subset of genes, those coding for the antioxidants catalase, sulfiredoxin or thioredoxin reductase, do need oxidized Pap1 to form a heterodimer with the constitutively nuclear transcription factor Prr1. The ability of Pap1 to bind and activate drug tolerance promoters is independent on Prr1, whereas its affinity for the antioxidant promoters is significantly enhanced upon association with Prr1. This finding suggests that the activation of both antioxidant and drug resistance genes in response to oxidative stress share a common inducer, H2O2, but alternative effectors.Spanish Ministry of Science and Innovation (BFU2009-06933), PLAN E and FEDER, by the Spanish program Consolider-Ingenio 2010 Grant CSD 2007-0020, and by SGR2009-196 from Generalitat de Catalunya (Spain) to E.H; ICREA Academia Awards (Generalitat de Catalunya) to E. H. and J.A.; pre-doctoral fellowship (FPI) and a post-doctoral contract Juan de la Cierva, respectively, from the Ministerio de Ciencia e Innovación (Spain) to I.A.C. and P.G. Funding for this work and for open access charge: Spanish Ministry of Science and Innovatio