Abstract
Ixr1 is a Saccharomyces cerevisiae HMGB protein that regulates the hypoxic regulon and also controls the expression of other genes involved in the oxidative stress response or re-adaptation of catabolic and anabolic fluxes when oxygen is limiting. Ixr1 also binds with high affinity to cisplatin-DNA adducts and modulates DNA repair. The influence of Ixr1 on transcription in the absence or presence of cisplatin has been analyzed in this work. Ixr1 regulates other transcriptional factors that respond to nutrient availability or extracellular and intracellular stress stimuli, some controlled by the TOR pathway and PKA signaling. Ixr1 controls transcription of ribosomal RNAs and genes encoding ribosomal proteins or involved in ribosome assembly. qPCR, ChIP, and 18S and 25S rRNAs measurement have confirmed this function. Ixr1 binds directly to several promoters of genes related to rRNA transcription and ribosome biogenesis. Cisplatin treatment mimics the effect of IXR1 deletion on rRNA and ribosomal gene transcription, and prevents Ixr1 binding to specific promoters related to these processes.
Highlights
The high-mobility group (HMG) proteins, present in almost all metazoans and plants, were discovered as nuclear factors over 40 years ago[1]
Several differences between differentially expressed genes (DEGs), reported in our study in a W303 genetic background and a previous report on a BY4741 genetic background[10], concern genes from the ergosterol biosynthetic pathway (ERG28, NCP1 MCR1, ERG5, ERG24 and ERG10), which are downregulated in W303-ixrΔ but unaffected in BY474-ixrΔ10. These genes are regulated by 2 homologous transcriptional factors, Ecm[22] and Upc[2], that bind to their target promoters under normoxia or hypoxia, respectively[23], and which regulate Ixr[1] expression[8]
Distribution of downregulated genes in enriched functional groups, analyzed with FUNSPEC, includes GO-terms associated with ribosome biogenesis, translation, metabolism of amino acids, membrane transport or ion channels (Fig. 1C)
Summary
The high-mobility group (HMG) proteins, present in almost all metazoans and plants, were discovered as nuclear factors over 40 years ago[1]. The HMG-box that characterizes the HMGB subfamily[2] comprises 3 α-helices folded into an L-shaped configuration, in which the concave surface binds to the minor groove of DNA3 They act in the nucleus as non-histone architectural-chromatin proteins, having regulatory functions in replication, transcription and DNA repair[4]. The hypothesis that Ixr[1] and other HMG-domain proteins might block repair of the major cisplatin-DNA adducts in vivo, inducing cell death, was postulated over 20 years ago[20]. Connections between this control, the TOR signaling pathway and the effects of cisplatin are discussed
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