Dual function of Ixr1 in transcriptional regulation and recognition of cisplatin-DNA adducts is caused by differential binding through its two HMG-boxes

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.

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“…These results confirm and extend the role of Ixr1 as a transcriptional regulator in S . cerevisiae 6 – 10 , 12 .…”

Section: Resultsmentioning

confidence: 99%

“…Ixr1 also binds to cisplatin-DNA adducts with high affinity 11 . A model to explain the dual role of Ixr1 in transcriptional regulation and recognition of cisplatin-DNA adducts has recently been proposed 12 .…”

Section: Introductionmentioning

confidence: 99%

Ixr1 Regulates Ribosomal Gene Transcription and Yeast Response to Cisplatin

Vizoso-Vázquez

Lamas-Maceiras

González-Siso

et al. 2018

Sci Rep

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“…With the exception of Rox1 that behaves as a specific transcriptional regulator of the hypoxic yeast regulon [14] and Ixr1 that has a dual function as specific transcription factor and DNAbinding protein without sequence specificity, also participating in DNA repair [15], the other HMGB proteins from S. cerevisiae might be considered as chromatin architectural proteins, but with wide influence on gene expression [16]. This is not a HMGB-exclusive mechanism since, in eukaryotes, many other chromatin components, such as histones [17], histone chaperones and modifiers [18], chromatin remodel complexes [19], and long noncoding RNAs [20], affect gene expression by different mechanisms.…”

Section: Hmgb Proteins From Saccharomyces Cerevisiaementioning

confidence: 99%

“…We have recently evidenced that functional specialization of the 2 HMG boxes, which are present in Ixr1, may explain its dual function. Regulation of transcription and DNA repair is achieved through differential recognition of specific regulatory sequences in the target promoters, or DNA disturbances caused by cisplatin treatment [15].…”

Section: Direct Binding To Target Promotersmentioning

confidence: 99%

HMGB Proteins from Yeast to Human. Gene Regulation, DNA Repair and Beyond

Vizoso-Vázquez¹,

Barreiro-Alonso²,

Rico-Díaz³

et al. 2017

Old Yeasts - New Questions

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HMGB proteins are characterized for containing one or more HMG-box domains and are well conserved from yeasts to higher eukaryotes. The HMG-box domain is formed by three α-helices with an L-shaped fold. Although HMGB proteins also have cytoplasmic and extracellular functions, they bind to nuclear or mitochondrial DNA in a highly dynamic process that affects chromatin organization. In this review, we mainly focus on HMGB proteins from yeast and their human homologs as functionally involved in DNA repair and transcriptional regulation. Recent research reveals that these proteins participate in epigenetic control of gene expression, aging, disease, or stem-cell biology.

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“…The HMGB protein family is characterized for presenting one or more HMG-box domains with DNA/RNA binding abilities. In multicellular eukaryotes, these proteins are implicated not only in many DNA-dependent nuclear processes at the chromatin level [ 6 ] (sequence and non-sequence specific), but also in the cytoplasm [ 7 ], or extracellularly acting in cell signaling and inflammation [ 8 ]. In the nucleus HMGB proteins from yeast and other higher eukaryotes are functionally involved in chromatin interactions, DNA repair, transcriptional regulation, and epigenetic control of gene expression.…”

Section: Introductionmentioning

confidence: 99%

The HMGB Protein KlIxr1, a DNA Binding Regulator of Kluyveromyces lactis Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis

et al. 2021

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In the traditional fermentative model yeast Saccharomyces cerevisiae, ScIxr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. Kluyveromyces lactis is also a useful eukaryotic model, more similar to many human cells due to its respiratory metabolism. We cloned and functionally characterized by different methodologies KlIXR1, which encodes a protein with only 34.4% amino acid sequence similarity to ScIxr1. Our data indicate that both proteins share common functions, including their involvement in the response to hypoxia or oxidative stress induced by hydrogen peroxide or metal treatments, as well as in the control of key regulators for maintenance of the dNTP (deoxyribonucleotide triphosphate) pool and ribosome synthesis. KlIxr1 is able to bind specific regulatory DNA sequences in the promoter of its target genes, which are well conserved between S. cerevisiae and K. lactis. Oppositely, we found important differences between ScIrx1 and KlIxr1 affecting cellular responses to cisplatin or cycloheximide in these yeasts, which could be dependent on specific and non-conserved domains present in these two proteins.

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Dual function of Ixr1 in transcriptional regulation and recognition of cisplatin-DNA adducts is caused by differential binding through its two HMG-boxes

Cited by 10 publications

References 69 publications

Ixr1 Regulates Ribosomal Gene Transcription and Yeast Response to Cisplatin

Ixr1 Regulates Ribosomal Gene Transcription and Yeast Response to Cisplatin

HMGB Proteins from Yeast to Human. Gene Regulation, DNA Repair and Beyond

The HMGB Protein KlIxr1, a DNA Binding Regulator of Kluyveromyces lactis Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis

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