{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T23:40:00Z","timestamp":1778110800643,"version":"3.51.4"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,10,13]],"date-time":"2016-10-13T00:00:00Z","timestamp":1476316800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,10,13]],"date-time":"2016-10-13T00:00:00Z","timestamp":1476316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Valproic acid (VA) is a pharmacologically important histone deacetylase inhibitor that recently garnered attention as an anticancer agent. Since the molecular mechanisms behind the multiple effects of VA are unclear, this study was aimed to unravel the comprehensive cellular processes affected by VA and its molecular targets <jats:italic>in vivo<\/jats:italic> using budding yeast as a model organism. Interestingly, genome-wide transcriptome analysis of cells treated with VA showed differential regulation of 30% of the genome. Functional enrichment analysis of VA transcriptome evidenced alteration of various cellular processes including cell cycle, cell wall biogenesis, DNA repair, ion homeostasis, metabolism, stress response, transport and ribosomal biogenesis, etc. Moreover, our genetic screening analysis revealed VA molecular targets belonging to oxidative and osmotic stress, DNA repair, cell wall integrity, and iron homeostasis. Further, our results demonstrated the activation of mitogen-activated protein kinases (MAPKs) Hog1 (<jats:italic>p38<\/jats:italic>) and Slt2 (<jats:italic>p44\/42<\/jats:italic>) upon VA treatment. Our results also exhibited that VA acts through alteration of mitochondrial, ER architecture and functions. Especially, VA effects were neutralized in cells lacking lipid particles. Altogether, our results deciphered the novel molecular insights and mechanistic links to strengthen our knowledge on diverse cellular effects of VA along with its probable therapeutic targets and detoxification approaches.<\/jats:p>","DOI":"10.1038\/srep35322","type":"journal-article","created":{"date-parts":[[2016,10,13]],"date-time":"2016-10-13T09:32:00Z","timestamp":1476351120000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Combined Transcriptomics and Chemical-Genetics Reveal Molecular Mode of Action of Valproic acid, an Anticancer Molecule using Budding Yeast Model"],"prefix":"10.1038","volume":"6","author":[{"given":"Upendarrao","family":"Golla","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepthi","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghuvir Singh","family":"Tomar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,10,13]]},"reference":[{"key":"BFsrep35322_CR1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/47412","volume":"403","author":"BD Strahl","year":"2000","unstructured":"Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41\u201345, doi: 10.1038\/47412 (2000).","journal-title":"Nature"},{"key":"BFsrep35322_CR2","unstructured":"Mandal, P. et al. In Molecular mechanisms and physiology of disease: Implications for Epigenetics and Health (eds Nilanjana, Maulik & Tom, Karagiannis ) 113\u2013126 (Springer: New York,, 2014)."},{"key":"BFsrep35322_CR3","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/nrg3055","volume":"12","author":"E de Nadal","year":"2011","unstructured":"de Nadal, E., Ammerer, G. & Posas, F. Controlling gene expression in response to stress. Nat Rev Genet 12, 833\u2013845, doi: 10.1038\/nrg3055 (2011).","journal-title":"Nat Rev Genet"},{"key":"BFsrep35322_CR4","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.molonc.2012.09.004","volume":"6","author":"A Nebbioso","year":"2012","unstructured":"Nebbioso, A., Carafa, V., Benedetti, R. & Altucci, L. Trials with \u2018epigenetic\u2019 drugs: An update. Molecular Oncology 6, 657\u2013682, doi: 10.1016\/j.molonc.2012.09.004 (2012).","journal-title":"Molecular Oncology"},{"key":"BFsrep35322_CR5","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1158\/1541-7786.MCR-07-0324","volume":"5","author":"M Dokmanovic","year":"2007","unstructured":"Dokmanovic, M., Clarke, C. & Marks, P. A. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5, 981\u2013989, doi: 10.1158\/1541-7786.MCR-07-0324 (2007).","journal-title":"Mol Cancer Res"},{"key":"BFsrep35322_CR6","doi-asserted-by":"crossref","unstructured":"Chateauvieux, S., Morceau, F., Dicato, M. & Diederich, M. Molecular and Therapeutic Potential and Toxicity of Valproic Acid. Journal of Biomedicine and Biotechnology, doi: Artn 479364 10.1155\/2010\/479364 (2010).","DOI":"10.1155\/2010\/479364"},{"key":"BFsrep35322_CR7","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1080\/03602530701690341","volume":"39","author":"H Mori","year":"2007","unstructured":"Mori, H., Takahashi, K. & Mizutani, T. Interaction between valproic acid and carbapenem antibiotics. Drug Metabolism Reviews 39, 647\u2013657, doi: 10.1080\/03602530701690341 (2007).","journal-title":"Drug Metabolism Reviews"},{"key":"BFsrep35322_CR8","doi-asserted-by":"publisher","first-page":"361","DOI":"10.2174\/138945010790711923","volume":"11","author":"J Hrebackova","year":"2010","unstructured":"Hrebackova, J., Hrabeta, J. & Eckschlager, T. Valproic acid in the complex therapy of malignant tumors. Curr Drug Targets 11, 361\u2013379 (2010).","journal-title":"Curr Drug Targets"},{"key":"BFsrep35322_CR9","doi-asserted-by":"publisher","first-page":"36734","DOI":"10.1074\/jbc.M101287200","volume":"276","author":"CJ Phiel","year":"2001","unstructured":"Phiel, C. J. et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. Journal of Biological Chemistry 276, 36734\u201336741, doi: 10.1074\/jbc.M101287200 (2001).","journal-title":"Journal of Biological Chemistry"},{"key":"BFsrep35322_CR10","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1046\/j.1471-4159.2000.0721327.x","volume":"72","author":"G Chen","year":"1999","unstructured":"Chen, G., Huang, L. D., Jiang, Y. M. & Manji, H. K. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 72, 1327\u20131330 (1999).","journal-title":"J Neurochem"},{"key":"BFsrep35322_CR11","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1534\/genetics.111.130765","volume":"189","author":"D Botstein","year":"2011","unstructured":"Botstein, D. & Fink, G. R. Yeast: an experimental organism for 21st Century biology. Genetics 189, 695\u2013704, doi: 10.1534\/genetics.111.130765 (2011).","journal-title":"Genetics"},{"key":"BFsrep35322_CR12","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/ng1042","volume":"32","author":"DL Gerhold","year":"2002","unstructured":"Gerhold, D. L., Jensen, R. V. & Gullans, S. R. Better therapeutics through microarrays. Nat Genet 32, 547\u2013552, doi: 10.1038\/ng1042 (2002).","journal-title":"Nat Genet"},{"key":"BFsrep35322_CR13","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1016\/j.mib.2013.07.020","volume":"16","author":"CE Outten","year":"2013","unstructured":"Outten, C. E. & Albetel, A. N. Iron sensing and regulation in Saccharomyces cerevisiae: Ironing out the mechanistic details. Curr Opin Microbiol 16, 662\u2013668, doi: 10.1016\/j.mib.2013.07.020 (2013).","journal-title":"Curr Opin Microbiol"},{"key":"BFsrep35322_CR14","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1006\/abbi.2001.2671","volume":"397","author":"H Atamna","year":"2002","unstructured":"Atamna, H., Walter, P. B. & Ames, B. N. The role of heme and iron-sulfur clusters in mitochondrial biogenesis, maintenance, and decay with age. Arch Biochem Biophys 397, 345\u2013353, doi: 10.1006\/abbi.2001.2671 (2002).","journal-title":"Arch Biochem Biophys"},{"key":"BFsrep35322_CR15","doi-asserted-by":"publisher","first-page":"40131","DOI":"10.1074\/jbc.M112.399428","volume":"287","author":"EY Chan","year":"2012","unstructured":"Chan, E. Y. & McQuibban, G. A. Phosphatidylserine decarboxylase 1 (Psd1) promotes mitochondrial fusion by regulating the biophysical properties of the mitochondrial membrane and alternative topogenesis of mitochondrial genome maintenance protein 1 (Mgm1). Journal of Biological Chemistry 287, 40131\u201340139, doi: 10.1074\/jbc.M112.399428 (2012).","journal-title":"Journal of Biological Chemistry"},{"key":"BFsrep35322_CR16","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/j.febslet.2004.12.051","volume":"579","author":"K Mitsui","year":"2005","unstructured":"Mitsui, K., Nakagawa, D., Nakamura, M., Okamoto, T. & Tsurugi, K. Valproic acid induces apoptosis dependent of Yca1p at concentrations that mildly affect the proliferation of yeast. Febs Letters 579, 723\u2013727, doi: 10.1016\/j.febslet.2004.12.051 (2005).","journal-title":"Febs Letters"},{"key":"BFsrep35322_CR17","doi-asserted-by":"publisher","first-page":"d963","DOI":"10.2741\/1109","volume":"8","author":"DM Wilson 3rd","year":"2003","unstructured":"Wilson, D. M. 3rd, Sofinowski, T. M. & McNeill, D. R. Repair mechanisms for oxidative DNA damage. Front Biosci 8, d963\u2013d981 (2003).","journal-title":"Front Biosci"},{"key":"BFsrep35322_CR18","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1016\/j.dnarep.2009.04.021","volume":"8","author":"CD Putnam","year":"2009","unstructured":"Putnam, C. D., Jaehnig, E. J. & Kolodner, R. D. Perspectives on the DNA damage and replication checkpoint responses in Saccharomyces cerevisiae. DNA Repair 8, 974\u2013982, doi: 10.1016\/j.dnarep.2009.04.021 (2009).","journal-title":"DNA Repair"},{"key":"BFsrep35322_CR19","doi-asserted-by":"publisher","first-page":"6490","DOI":"10.1093\/nar\/gkq552","volume":"38","author":"BL Andreson","year":"2010","unstructured":"Andreson, B. L., Gupta, A., Georgieva, B. P. & Rothstein, R. The ribonucleotide reductase inhibitor, Sml1, is sequentially phosphorylated, ubiquitylated and degraded in response to DNA damage. Nucleic Acids Res 38, 6490\u20136501, doi: 10.1093\/nar\/gkq552 (2010).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep35322_CR20","doi-asserted-by":"publisher","first-page":"3259","DOI":"10.1128\/MCB.00472-14","volume":"34","author":"N Sanvisens","year":"2014","unstructured":"Sanvisens, N. et al. Yeast Dun1 kinase regulates ribonucleotide reductase inhibitor Sml1 in response to iron deficiency. Mol Cell Biol 34, 3259\u20133271, doi: 10.1128\/MCB.00472-14 (2014).","journal-title":"Mol Cell Biol"},{"key":"BFsrep35322_CR21","doi-asserted-by":"publisher","first-page":"15466","DOI":"10.1074\/jbc.M004179200","volume":"276","author":"DL Vaden","year":"2001","unstructured":"Vaden, D. L., Ding, D., Peterson, B. & Greenberg, M. L. Lithium and valproate decrease inositol mass and increase expression of the yeast INO1 and INO2 genes for inositol biosynthesis. Journal of Biological Chemistry 276, 15466\u201315471, doi: 10.1074\/jbc.M004179200 (2001).","journal-title":"Journal of Biological Chemistry"},{"key":"BFsrep35322_CR22","doi-asserted-by":"publisher","first-page":"3119","DOI":"10.1093\/emboj\/18.11.3119","volume":"18","author":"TN Gonzalez","year":"1999","unstructured":"Gonzalez, T. N., Sidrauski, C., Dorfler, S. & Walter, P. Mechanism of non-spliceosomal mRNA splicing in the unfolded protein response pathway. EMBO J 18, 3119\u20133132, doi: 10.1093\/emboj\/18.11.3119 (1999).","journal-title":"EMBO J"},{"key":"BFsrep35322_CR23","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1016\/j.febslet.2014.09.021","volume":"588","author":"AN Jensen","year":"2014","unstructured":"Jensen, A. N., Chindaudomsate, W., Thitiananpakorn, K., Mongkolsuk, S. & Jensen, L. T. Improper protein trafficking contributes to artemisinin sensitivity in cells lacking the KDAC Rpd3p. Febs Letters 588, 4018\u20134025, doi: 10.1016\/j.febslet.2014.09.021 (2014).","journal-title":"Febs Letters"},{"key":"BFsrep35322_CR24","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1091\/mbc.E14-11-1559","volume":"26","author":"HG Suresh","year":"2015","unstructured":"Suresh, H. G. et al. Prolonged starvation drives reversible sequestration of lipid biosynthetic enzymes and organelle reorganization in Saccharomyces cerevisiae. Mol Biol Cell 26, 1601\u20131615, doi: 10.1091\/mbc.E14-11-1559 (2015).","journal-title":"Mol Biol Cell"},{"key":"BFsrep35322_CR25","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1074\/jbc.M110.172296","volume":"286","author":"ML Gaspar","year":"2011","unstructured":"Gaspar, M. L., Hofbauer, H. F., Kohlwein, S. D. & Henry, S. A. Coordination of storage lipid synthesis and membrane biogenesis: evidence for cross-talk between triacylglycerol metabolism and phosphatidylinositol synthesis. Journal of Biological Chemistry 286, 1696\u20131708, doi: 10.1074\/jbc.M110.172296 (2011).","journal-title":"Journal of Biological Chemistry"},{"key":"BFsrep35322_CR26","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1534\/genetics.107.070946","volume":"175","author":"M Miyatake","year":"2007","unstructured":"Miyatake, M. et al. Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast. Genetics 175, 1695\u20131705, doi: 10.1534\/genetics.107.070946 (2007).","journal-title":"Genetics"},{"key":"BFsrep35322_CR27","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1128\/MMBR.69.2.262-291.2005","volume":"69","author":"DE Levin","year":"2005","unstructured":"Levin, D. E. Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 69, 262\u2013291, doi: 10.1128\/MMBR.69.2.262-291.2005 (2005).","journal-title":"Microbiol Mol Biol Rev"},{"key":"BFsrep35322_CR28","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.neulet.2010.07.004","volume":"482","author":"N Xie","year":"2010","unstructured":"Xie, N. et al. The role of p38 MAPK in valproic acid induced microglia apoptosis. Neurosci Lett 482, 51\u201356, doi: 10.1016\/j.neulet.2010.07.004 (2010).","journal-title":"Neurosci Lett"},{"key":"BFsrep35322_CR29","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1128\/MMBR.62.4.1264-1300.1998","volume":"62","author":"MC Gustin","year":"1998","unstructured":"Gustin, M. C., Albertyn, J., Alexander, M. & Davenport, K. MAP kinase pathways in the yeast Saccharomyces cerevisiae. Microbiol Mol Biol Rev 62, 1264\u20131300 (1998).","journal-title":"Microbiol Mol Biol Rev"},{"key":"BFsrep35322_CR30","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1128\/MCB.21.1.51-60.2001","volume":"21","author":"J Warmka","year":"2001","unstructured":"Warmka, J., Hanneman, J., Lee, J., Amin, D. & Ota, I. Ptc1, a type 2C Ser\/Thr phosphatase, inactivates the HOG pathway by dephosphorylating the mitogen-activated protein kinase Hog1. Mol Cell Biol 21, 51\u201360, doi: 10.1128\/MCB.21.1.51-60.2001 (2001).","journal-title":"Mol Cell Biol"},{"key":"BFsrep35322_CR31","unstructured":"Gasch, A. P. In Yeast Stress Responses (eds Stefan, Hohmann & Willem H., Mager ) 11\u201370 (Springer Berlin Heidelberg, 2003)."},{"key":"BFsrep35322_CR32","doi-asserted-by":"publisher","first-page":"20130950","DOI":"10.1098\/rsif.2013.0950","volume":"11","author":"G Hong","year":"2014","unstructured":"Hong, G., Zhang, W., Li, H., Shen, X. & Guo, Z. Separate enrichment analysis of pathways for up- and downregulated genes. J R Soc Interface 11, 20130950, doi: 10.1098\/rsif.2013.0950 (2014).","journal-title":"J R Soc Interface"},{"key":"BFsrep35322_CR33","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s13277-010-0126-5","volume":"32","author":"X Zhao","year":"2011","unstructured":"Zhao, X. et al. The G1 phase arrest and apoptosis by intrinsic pathway induced by valproic acid inhibit proliferation of BGC-823 gastric carcinoma cells. Tumour Biol 32, 335\u2013346, doi: 10.1007\/s13277-010-0126-5 (2011).","journal-title":"Tumour Biol"},{"key":"BFsrep35322_CR34","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.taap.2011.03.004","volume":"252","author":"TK Kiang","year":"2011","unstructured":"Kiang, T. K. et al. Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity. Toxicol Appl Pharmacol 252, 318\u2013324, doi: 10.1016\/j.taap.2011.03.004 (2011).","journal-title":"Toxicol Appl Pharmacol"},{"key":"BFsrep35322_CR35","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.molcel.2004.08.025","volume":"15","author":"CM Haynes","year":"2004","unstructured":"Haynes, C. M., Titus, E. A. & Cooper, A. A. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 15, 767\u2013776, doi: 10.1016\/j.molcel.2004.08.025 (2004).","journal-title":"Mol Cell"},{"key":"BFsrep35322_CR36","doi-asserted-by":"publisher","first-page":"268","DOI":"10.5414\/CP201466","volume":"49","author":"S Ounjaijean","year":"2011","unstructured":"Ounjaijean, S. et al. Increase in non-transferrin bound iron and the oxidative stress status in epilepsy patients treated using valproic acid monotherapy. Int J Clin Pharmacol Ther 49, 268\u2013276, doi: 10.5414\/CP201466 (2011).","journal-title":"Int J Clin Pharmacol Ther"},{"key":"BFsrep35322_CR37","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1212\/WNL.36.3.351","volume":"36","author":"K Hayasaka","year":"1986","unstructured":"Hayasaka, K. et al. Effects of valproate on biogenesis and function of liver mitochondria. Neurology 36, 351\u2013356 (1986).","journal-title":"Neurology"},{"key":"BFsrep35322_CR38","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.ejphar.2012.06.019","volume":"690","author":"H Chen","year":"2012","unstructured":"Chen, H., Dzitoyeva, S. & Manev, H. Effect of valproic acid on mitochondrial epigenetics. Eur J Pharmacol 690, 51\u201359, doi: 10.1016\/j.ejphar.2012.06.019 (2012).","journal-title":"Eur J Pharmacol"},{"key":"BFsrep35322_CR39","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.tem.2009.12.006","volume":"21","author":"A Sheftel","year":"2010","unstructured":"Sheftel, A., Stehling, O. & Lill, R. Iron-sulfur proteins in health and disease. Trends in endocrinology and metabolism: TEM 21, 302\u2013314, doi: 10.1016\/j.tem.2009.12.006 (2010).","journal-title":"Trends in endocrinology and metabolism: TEM"},{"key":"BFsrep35322_CR40","doi-asserted-by":"publisher","first-page":"27460","DOI":"10.1074\/jbc.M115.683706","volume":"290","author":"RM Deranieh","year":"2015","unstructured":"Deranieh, R. M. et al. Perturbation of the Vacuolar ATPase: A NOVEL CONSEQUENCE OF INOSITOL DEPLETION. Journal of Biological Chemistry 290, 27460\u201327472, doi: 10.1074\/jbc.M115.683706 (2015).","journal-title":"Journal of Biological Chemistry"},{"key":"BFsrep35322_CR41","doi-asserted-by":"publisher","first-page":"e68738","DOI":"10.1371\/journal.pone.0068738","volume":"8","author":"L Zhang","year":"2013","unstructured":"Zhang, L., Ma, N., Liu, Q. & Ma, Y. Genome-wide screening for genes associated with valproic acid sensitivity in fission yeast. Plos One 8, e68738, doi: 10.1371\/journal.pone.0068738 (2013).","journal-title":"Plos One"},{"key":"BFsrep35322_CR42","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1089\/neu.2013.3146","volume":"31","author":"JY Lee","year":"2014","unstructured":"Lee, J. Y. et al. Valproic acid protects motor neuron death by inhibiting oxidative stress and endoplasmic reticulum stress-mediated cytochrome C release after spinal cord injury. J Neurotrauma 31, 582\u2013594, doi: 10.1089\/neu.2013.3146 (2014).","journal-title":"J Neurotrauma"},{"key":"BFsrep35322_CR43","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1016\/j.bbamcr.2008.01.005","volume":"1783","author":"B Almeida","year":"2008","unstructured":"Almeida, B. et al. Drug-induced apoptosis in yeast. Biochim Biophys Acta 1783, 1436\u20131448, doi: 10.1016\/j.bbamcr.2008.01.005 (2008).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep35322_CR44","doi-asserted-by":"publisher","first-page":"S311","DOI":"10.1194\/jlr.R800049-JLR200","volume":"50","author":"P Fagone","year":"2009","unstructured":"Fagone, P. & Jackowski, S. Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res 50 Suppl, S311\u2013S316, doi: 10.1194\/jlr.R800049-JLR200 (2009).","journal-title":"J Lipid Res"},{"key":"BFsrep35322_CR45","doi-asserted-by":"publisher","first-page":"3991","DOI":"10.1016\/j.febslet.2007.07.030","volume":"581","author":"Q Sun","year":"2007","unstructured":"Sun, Q., Bi, L., Su, X., Tsurugi, K. & Mitsui, K. Valproate induces apoptosis by inducing accumulation of neutral lipids which was prevented by disruption of the SIR2 gene in Saccharomyces cerevisiae. Febs Letters 581, 3991\u20133995, doi: 10.1016\/j.febslet.2007.07.030 (2007).","journal-title":"Febs Letters"},{"key":"BFsrep35322_CR46","doi-asserted-by":"publisher","first-page":"4257","DOI":"10.1093\/nar\/gkh717","volume":"32","author":"E Haghnazari","year":"2004","unstructured":"Haghnazari, E. & Heyer, W. D. The DNA damage checkpoint pathways exert multiple controls on the efficiency and outcome of the repair of a double-stranded DNA gap. Nucleic Acids Res 32, 4257\u20134268, doi: 10.1093\/nar\/gkh717 (2004).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep35322_CR47","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1097\/SHK.0b013e31822f7e58","volume":"36","author":"S Sugiura","year":"2011","unstructured":"Sugiura, S. et al. Valproic Acid Increases Susceptibility to Endotoxin Shock through Enhanced Release of High-Mobility Group Box 1. Shock 36, 494\u2013500, doi: 10.1097\/SHK.0b013e31822f7e58 (2011).","journal-title":"Shock"},{"key":"BFsrep35322_CR48","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/S0168-9525(02)02723-3","volume":"18","author":"SM O\u2019Rourke","year":"2002","unstructured":"O\u2019Rourke, S. M., Herskowitz, I. & O\u2019Shea, E. K. Yeast go the whole HOG for the hyperosmotic response. Trends Genet 18, 405\u2013412 (2002).","journal-title":"Trends Genet"},{"key":"BFsrep35322_CR49","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1002\/yea.1792","volume":"27","author":"JM Rodriguez-Pena","year":"2010","unstructured":"Rodriguez-Pena, J. M., Garcia, R., Nombela, C. & Arroyo, J. The high-osmolarity glycerol (HOG) and cell wall integrity (CWI) signalling pathways interplay: a yeast dialogue between MAPK routes. Yeast 27, 495\u2013502, doi: 10.1002\/yea.1792 (2010).","journal-title":"Yeast"},{"key":"BFsrep35322_CR50","doi-asserted-by":"publisher","first-page":"2616","DOI":"10.1074\/jbc.M306110200","volume":"279","author":"JC Harrison","year":"2004","unstructured":"Harrison, J. C., Zyla, T. R., Bardes, E. S. & Lew, D. J. Stress-specific activation mechanisms for the \u201ccell integrity\u201d MAPK pathway. Journal of Biological Chemistry 279, 2616\u20132622, doi: 10.1074\/jbc.M306110200 (2004).","journal-title":"Journal of Biological Chemistry"},{"key":"BFsrep35322_CR51","unstructured":"Golla, U., Joseph, D. & Tomar, R. S. In YEAST. S179-S180 (WILEY-BLACKWELL 111 RIVER ST, HOBOKEN 07030-5774, NJ USA)."},{"key":"BFsrep35322_CR52","doi-asserted-by":"crossref","unstructured":"Poster Sessions. Yeast32 Suppl 1, S93\u2013S272, doi: 10.1002\/yea.3092 (2015).","DOI":"10.1002\/yea.3092"},{"key":"BFsrep35322_CR53","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.fob.2014.01.002","volume":"4","author":"GK Azad","year":"2014","unstructured":"Azad, G. K. et al. Ebselen induces reactive oxygen species (ROS)-mediated cytotoxicity in Saccha-romyces cerevisiae with inhibition of glutamate dehydrogenase being a target. Febs Open Bio 4, 77\u201389, doi: 10.1016\/j.fob.2014.01.002 (2014).","journal-title":"Febs Open Bio"},{"key":"BFsrep35322_CR54","doi-asserted-by":"crossref","unstructured":"Azad, G. K., Singh, V., Golla, U. & Tomar, R. S. Depletion of Cellular Iron by Curcumin Leads to Alteration in Histone Acetylation and Degradation of Sml1p in Saccharomyces cerevisiae. Plos One 8, doi: ARTN e59003 10.1371\/journal.pone.0059003 (2013).","DOI":"10.1371\/journal.pone.0059003"},{"key":"BFsrep35322_CR55","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1021\/acs.chemrestox.5b00071","volume":"28","author":"U Golla","year":"2015","unstructured":"Golla, U., Bandi, G. & Tomar, R. S. Molecular Cytotoxicity Mechanisms of Allyl Alcohol (Acrolein) in Budding Yeast. Chemical Research in Toxicology 28, 1246\u20131264, doi: 10.1021\/acs.chemrestox.5b00071 (2015).","journal-title":"Chemical Research in Toxicology"},{"key":"BFsrep35322_CR56","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(T)(-Delta Delta C) method. Methods 25, 402\u2013408, doi: 10.1006\/meth.2001.1262 (2001).","journal-title":"Methods"},{"key":"BFsrep35322_CR57","doi-asserted-by":"crossref","unstructured":"Golla, U. et al. Sen1p Contributes to Genomic Integrity by Regulating Expression of Ribonucleotide Reductase 1 (RNR1) in Saccharomyces cerevisiae. Plos One 8, doi: UNSP e64798 10.1371\/journal.pone.0064798 (2013).","DOI":"10.1371\/journal.pone.0064798"},{"key":"BFsrep35322_CR58","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/0076-6879(83)01013-7","volume":"101","author":"L Guarente","year":"1983","unstructured":"Guarente, L. Yeast promoters and lacZ fusions designed to study expression of cloned genes in yeast. Methods Enzymol 101, 181\u2013191 (1983).","journal-title":"Methods Enzymol"},{"key":"BFsrep35322_CR59","unstructured":"Miller, J. H. Experiments in molecular genetics (Cold Spring Harbor Laboratory, 1972)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep35322.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep35322","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep35322.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T02:25:29Z","timestamp":1672885529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep35322"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,13]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,16]]}},"alternative-id":["BFsrep35322"],"URL":"https:\/\/doi.org\/10.1038\/srep35322","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,13]]},"assertion":[{"value":"14 June 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 September 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"35322"}}