Abstract
We have been studying the action mechanisms of valproic acid (VPA) in fission yeast Schizosaccharomyces pombe by developing a genetic screen for mutants that show hypersensitivity to VPA. In the present study, we performed a genome-wide screen of 3004 haploid deletion strains and confirmed 148 deletion strains to be VPA sensitive. Of the 148 strains, 93 strains also showed sensitivity to another aliphatic acids HDAC inhibitor, sodium butyrate (SB), and 55 strains showed sensitivity to VPA but not to SB. Interestingly, we found that both VPA and SB treatment induced a marked increase in the transcription activity of Atf1 in wild-type cells. However, in clr6-1, a mutant allele the clr6+ gene encoding class I HDAC, neither VPA- nor SB induced the activation of Atf1 transcription activity. We also found that VPA, but not SB, caused an increase in cytoplasmic Ca2+ level. We further found that the cytoplasmic Ca2+ increase was caused by Ca2+ influx from extracellular medium via Cch1-Yam8 channel complex. Altogether, our present study indicates that VPA and SB play similar but distinct roles in multiple physiological processes in fission yeast.
Highlights
Introductionvalproic acid (VPA) is a short-chain branched fatty acid that was discovered serendipitously as an anticonvulsant while being used as a solvent
valproic acid (VPA) is a short-chain branched fatty acid that was discovered serendipitously as an anticonvulsant while being used as a solvent.Today VPA is used to treat a variety of psychiatric diseases such as seizure disorders, bipolar disorder and migraine [1,2], that is supposed by targeting GABA transaminase, succinate semialdehyde dehydrogenase, and alpha-ketoglutarate dehydrogenase andNa+ channels [3,4]
histone deacetylases (HDACs) inhibitors are divided into several structural classes including hydroximates, cyclic peptides, aliphatic acids, and benzamides [29,30,31]
Summary
VPA is a short-chain branched fatty acid that was discovered serendipitously as an anticonvulsant while being used as a solvent. The activity of class I and class II HDACs is inhibited by short chain fatty acids and hydroxamic acids, but class III HDACs are not inhibited by these agents [7]. HDACs catalyze the removal of the acetyl modification on lysine residues of histones, which is associated with a condensed chromatin structure resulting in the repression of gene transcription. HDAC inhibitors induce an increase in histone acetylation, which is associated with a loose chromatin structure thereby activating the transcription [8,9]. Histone proteins were the first and the most important targets of HDACs, increasing and SB increase the Atf transcriptional activity in a Clr6dependent manner. We found VPA, but not SB, caused Ca2+ influx via the Cch1-Yam channel complex
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