Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IMP dehydrogenase is a rate-limiting enzyme involved in the synthesis of GTP. In mammalian cells it is regulated with respect to growth rate and is the target of numerous therapeutic agents. Mutations in the RNA polymerase II elongation machinery render yeast sensitive to inhibitors of IMP dehydrogenase and defective in inducing transcription of one of the IMP dehydrogenase-encoding genes, IMD2. Here we show that loss of IMD2, but not IMD1, IMD3, or IMD4, conferred upon yeast the same drug sensitivity found in elongation mutants. We tested whether the drug sensitivity of elongation mutants is due to their inability to induce IMD2 by providing them with exogenous copies of the gene. In some elongation mutants, overexpression reversed drug sensitivity and a transcriptional defect. Overexpression in mutants with a more severe phenotype partially suppressed drug sensitivity but was inconsequential in reversing a defect in transcription. These findings suggest that the drug sensitivity of elongation mutants is largely but not solely attributable to defects in the ability to induce IMD2, because transcription is compromised even when IMD2 mRNA levels are adequate. We describe two DNA sequence elements in the promoter of the gene that regulate it. We also found that IMD2 mRNA abundance is coupled to cell growth rate. These findings show that yeast possess a conserved system that gauges nucleotide pools and cell growth rate and responds through a uniquely regulated member of the IMD gene family.
 ...
PMID:Regulation of an IMP dehydrogenase gene and its overexpression in drug-sensitive transcription elongation mutants of yeast. 1144 Oct 18

IMP dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo synthesis of guanine, namely the oxidation of IMP to XMP with a concomitant reduction of NAD+. In Saccharomyces cerevisiae, a family of four closely-related genes, IMD1, IMD2 (also known as PUR5), IMD3, and IMD4, encodes the putative IMPDH. Although IMPDH synthesizes guanine in the cytoplasm, it has also been found in the nucleus, where it associates with nucleic acids in human cells. Here, we further show that IMPDH is recruited to actively transcribed region of genes. A synthetic lethal screen using a deletion strain of Ctk1 kinase, a yeast homolog of mammalian Cdk9/P-TEFb that phosphorylates serine 2 within the RNA polymerase II (RNApII) C-terminal domain (CTD), identified that Imd2 genetically interacts with Ctk1. Consistent with this association, IMPDHs were recruited to elongating RNApII only when serine 2 of the CTD was phosphorylated by Ctk1. Loss of Imd2 had little effect on the association of most elongation factors with RNApII. However, in cells lacking Imd2 or all the essential IMPDHs in the presence of minimal guanine, a defect in the association of Ctk1 with the promoter region was seen. Taken together, our results show that IMPDH is recruited to transcription complex through serine 2 phosphorylation of RNApII CTD and suggest that it may play a role in initiating transcriptional regulation.
 ...
PMID:IMP dehydrogenase is recruited to the transcription complex through serine 2 phosphorylation of RNA polymerase II. 2009 57