Identifying Cis-Regulatory Changes Involved in the Evolution of Aerobic Fermentation in Yeasts

Lin, Zhenguo; Wang, Tzi‐Yuan; Tsai, Bing Shi; Wu, Fang Ting; Yu, Fu; Tseng, Yu Jung; Sung, Huang Mo; Li, Wen-Hsiung

doi:10.1093/gbe/evt067

Cited by 14 publications

(14 citation statements)

References 72 publications

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“…The effect of A35 on the binding of top2α to DNA was evaluated using an electrophoretic mobility shift (EMSA) kit (Invitrogen) as previously described [ 60 ] according to the manufacturer's protocol. Oligonucleotides containing a strong top2 binding site corresponding to residues 87–126 of the pBR322 plasmid were annealed, and 1 nm was incubated with nuclear extracts (5 μg) from K562 cells in reaction buffer (750 mM KCl, 0.5 mM dithiothreitol, 0.5 mM EDTA, 50 mM Tris, pH 7.4) on ice for 30 min.…”

Section: Methodsmentioning

confidence: 99%

The dual topoisomerase inhibitor A35 preferentially and specially targets topoisomerase 2α by enhancing pre-strand and post-strand cleavage and inhibiting DNA religation

Zhao

Jiang

et al. 2015

Oncotarget

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DNA topoisomerases play a key role in tumor proliferation. Chemotherapeutics targeting topoisomerases have been widely used in clinical oncology, but resistance and side effects, particularly cardiotoxicity, usually limit their application. Clinical data show that a decrease in topoisomerase (top) levels is the primary factor responsible for resistance, but in cells there is compensatory effect between the levels of top1 and top2α. Here, we validated cyclizing-berberine A35, which is a dual top inhibitor and preferentially targets top2α. The impact on the top2α catalytic cycle indicated that A35 could intercalate into DNA but did not interfere with DNA-top binding and top2α ATPase activity. A35 could facilitate DNA-top2α cleavage complex formation by enhancing pre-strand and post-strand cleavage and inhibiting religation, suggesting this compound can be a topoisomerase poison and had a district mechanism from other topoisomerase inhibitors. TARDIS and comet assays showed that A35 could induce cell DNA breakage and DNA-top complexes but had no effect on the cardiac toxicity inducer top2β. Silencing top1 augmented DNA break and silencing top2α decreased DNA break. Further validation in H9c2 cardiac cells showed A35 did not disturb cell proliferation and mitochondrial membrane potency. Additionally, an assay with nude mice further demonstrated A35 did not damage the heart. Our work identifies A35 as a novel skeleton compound dually inhibits topoisomerases, and predominantly and specially targets top2α by interfering with all cleavage steps and its no cardiac toxicity was verified by cardiac cells and mice heart. A35 could be a novel and effective targeting topoisomerase agent.

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Section: Methodsmentioning

confidence: 99%

The dual topoisomerase inhibitor A35 preferentially and specially targets topoisomerase 2α by enhancing pre-strand and post-strand cleavage and inhibiting DNA religation

Zhao

Jiang

et al. 2015

Oncotarget

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“…In contrast, physiological and metabolic traits have frequently evolved through changes in both protein-coding and cis-regulatory regions ( Ihmels et al. 2005 ; Lin et al. 2013 ; Roop et al.…”

Section: Introductionmentioning

confidence: 99%

Repeated Cis-Regulatory Tuning of a Metabolic Bottleneck Gene during Evolution

Kuang

Kominek

Alexander

et al. 2018

Molecular Biology and Evolution

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Repeated evolutionary events imply underlying genetic constraints that can make evolutionary mechanisms predictable. Morphological traits are thought to evolve frequently through cis-regulatory changes because these mechanisms bypass constraints in pleiotropic genes that are reused during development. In contrast, the constraints acting on metabolic traits during evolution are less well studied. Here we show how a metabolic bottleneck gene has repeatedly adopted similar cis-regulatory solutions during evolution, likely due to its pleiotropic role integrating flux from multiple metabolic pathways. Specifically, the genes encoding phosphoglucomutase activity (PGM1/PGM2), which connect GALactose catabolism to glycolysis, have gained and lost direct regulation by the transcription factor Gal4 several times during yeast evolution. Through targeted mutations of predicted Gal4-binding sites in yeast genomes, we show this galactose-mediated regulation of PGM1/2 supports vigorous growth on galactose in multiple yeast species, including Saccharomyces uvarum and Lachancea kluyveri. Furthermore, the addition of galactose-inducible PGM1 alone is sufficient to improve the growth on galactose of multiple species that lack this regulation, including Saccharomyces cerevisiae. The strong association between regulation of PGM1/2 by Gal4 even enables remarkably accurate predictions of galactose growth phenotypes between closely related species. This repeated mode of evolution suggests that this specific cis-regulatory connection is a common way that diverse yeasts can govern flux through the pathway, likely due to the constraints imposed by this pleiotropic bottleneck gene. Since metabolic pathways are highly interconnected, we argue that cis-regulatory evolution might be widespread at pleiotropic genes that control metabolic bottlenecks and intersections.

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“…Other studies have investigated the specific evolutionary patterns of TFs ( Coulombe-Huntington and Xia 2012 ) and of promoter sequences and TFBSs in the yeast genome ( Doniger and Fay 2007 ; Tirosh et al 2008 ; Tirosh, Barkai, et al 2009 ; Chen et al 2010 ; Tsai et al 2012 ; Lin et al 2013 ). A recent study found that regulatory motif variation is associated with gene expression differences between S. cerevisiae strains ( Connelly et al 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Gains and Losses of Transcription Factor Binding Sites inSaccharomyces cerevisiaeandSaccharomyces paradoxus

Schaefke

Wang²,

Wang³

et al. 2015

Genome Biol Evol

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Gene expression evolution occurs through changes in cis- or trans-regulatory elements or both. Interactions between transcription factors (TFs) and their binding sites (TFBSs) constitute one of the most important points where these two regulatory components intersect. In this study, we investigated the evolution of TFBSs in the promoter regions of different Saccharomyces strains and species. We divided the promoter of a gene into the proximal region and the distal region, which are defined, respectively, as the 200-bp region upstream of the transcription starting site and as the 200-bp region upstream of the proximal region. We found that the predicted TFBSs in the proximal promoter regions tend to be evolutionarily more conserved than those in the distal promoter regions. Additionally, Saccharomyces cerevisiae strains used in the fermentation of alcoholic drinks have experienced more TFBS losses than gains compared with strains from other environments (wild strains, laboratory strains, and clinical strains). We also showed that differences in TFBSs correlate with the cis component of gene expression evolution between species (comparing S. cerevisiae and its sister species Saccharomyces paradoxus) and within species (comparing two closely related S. cerevisiae strains).

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Identifying Cis-Regulatory Changes Involved in the Evolution of Aerobic Fermentation in Yeasts

Cited by 14 publications

References 72 publications

The dual topoisomerase inhibitor A35 preferentially and specially targets topoisomerase 2α by enhancing pre-strand and post-strand cleavage and inhibiting DNA religation

The dual topoisomerase inhibitor A35 preferentially and specially targets topoisomerase 2α by enhancing pre-strand and post-strand cleavage and inhibiting DNA religation

Repeated Cis-Regulatory Tuning of a Metabolic Bottleneck Gene during Evolution

Gains and Losses of Transcription Factor Binding Sites inSaccharomyces cerevisiaeandSaccharomyces paradoxus

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