Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TFIIH is a multisubunit complex, containing ATPase, helicases, and kinase activities. Functionally, TFIIH has been implicated in transcription by RNA polymerase II (RNAPII) and in nucleotide excision repair. A member of the cyclin-dependent kinase family, CDK7, is the kinase subunit of TFIIH. Genetically, CDK7 homologues have been implicated in transcription in Saccharomyces cerevisiae, and in mitotic regulation in Schizosaccharomyces pombe. Here we show that in mitosis the CDK7 subunit of TFIIH and the largest subunit of RNAPII become hyperphosphorylated. MPF-induced phosphorylation of CDK7 results in inhibition of the TFIIH-associated kinase and transcription activities. Negative and positive regulation of TFIIH requires phosphorylation within the T-loop of CDK7. Our data establishes TFIIH and its subunit CDK7 as a direct link between the regulation of transcription and the cell cycle.
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PMID:The molecular mechanism of mitotic inhibition of TFIIH is mediated by phosphorylation of CDK7. 983 6

RNA polymerase II nascent transcripts are capped during pausing before elongation. Here we report that hSPT5, the human homolog of yeast elongation factor SPT5, interacts directly with the capping enzyme. hSPT5 stimulated capping enzyme guanylylation and mRNA capping by severalfold. Although RNA 5'-triphosphatase activity was unaffected, binding to this domain in the full-length enzyme is likely involved in the stimulation, as hSPT5 did not increase the activity of the guanylyltransferase fragment. Consistent with capping enzyme binding, TFIIH-phosphorylated CTD stimulated guanylylation, and this increase was not additive with hSPT5.
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PMID:Transcription elongation factor hSPT5 stimulates mRNA capping. 1042 30

TFIIH is a multisubunit protein complex involved in RNA polymerase II transcription and nucleotide excision repair, which removes a wide variety of DNA lesions including UV-induced photoproducts. Mutations in the DNA-dependent ATPase/helicase subunits of TFIIH, XPB and XPD, are associated with three inherited syndromes as follows: xeroderma pigmentosum with or without Cockayne syndrome and trichothiodystrophy. By using epitope-tagged XPD we purified mammalian TFIIH carrying a wild type or an active-site mutant XPD subunit. Contrary to XPB, XPD helicase activity was dispensable for in vitro transcription, catalytic formation of trinucleotide transcripts, and promoter opening. Moreover, in contrast to XPB, microinjection of mutant XPD cDNA did not interfere with in vivo transcription. These data show directly that XPD activity is not required for transcription. However, during DNA repair, neither 5' nor 3' incisions in defined positions around a DNA adduct were detected in the presence of TFIIH containing inactive XPD, although substantial damage-dependent DNA synthesis was induced by the presence of mutant XPD both in cells and cell extracts. The aberrant damage-dependent DNA synthesis caused by the mutant XPD does not lead to effective repair, consistent with the discrepancy between repair synthesis and survival in cells from a number of XP-D patients.
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PMID:TFIIH with inactive XPD helicase functions in transcription initiation but is defective in DNA repair. 1066 May 93

The ATFa proteins, which are members of the CREB/ATF family of transcription factors, have previously been shown to interact with the adenovirus E1a oncoprotein and to mediate its transcriptional activity; they heterodimerize with Jun, Fos or related transcription factors, possibly altering their DNA-binding specificity; they also stably bind JNK2, a stress-induced protein kinase. Here we report the identification and characterization of a novel protein isolated in a yeast two-hybrid screen using the N-terminal half of ATFa as a bait. This 1306-residue protein (mAM, for mouse ATFa-associated Modulator) is rather acidic (pHi 4.5) and contains high proportions of Ser/Thr (21%) and Pro (11%) residues. It colocalizes and interacts with ATFa in mammalian cells, contains a bipartite nuclear localization signal and possesses an ATPase activity. Transfection experiments show that mAM is able to downregulate transcriptional activity, in an ATPase-independent manner. Our results indicate that mAM interacts with several components of the basal transcription machinery (TFIIE and TFIIH), including RNAPII itself. Together, these findings suggest that mAM may be involved in the fine-tuning of ATFa-regulated gene expression, by interfering with the assembly or stability of specific preinitiation transcription complexes.
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PMID:A murine ATFa-associated factor with transcriptional repressing activity. 1077 15

The peroxisome proliferator-activated receptor gamma (PPARgamma) regulates adipogenesis, lipid metabolism, and glucose homeostasis, and roles have emerged for this receptor in the pathogenesis and treatment of diabetes, atherosclerosis, and cancer. We report here that induction of the PPARgamma activator and adipogenesis forced by overexpression of adipogenic regulatory proteins is blocked upon expression of dominant-negative BRG1 or hBRM, the ATPase subunits of distinct SWI/SNF chromatin-remodeling enzymes. We demonstrate that histone hyperacetylation and the binding of C/EBP activators, polymerase II (Pol II), and general transcription factors (GTFs) initially occurred at the inducible PPARgamma2 promoter in the absence of SWI/SNF function. However, the polymerase and GTFs were subsequently lost from the promoter in cells expressing dominant-negative SWI/SNF, explaining the inhibition of PPARgamma2 expression. To corroborate these data, we analyzed interactions at the PPARgamma2 promoter in differentiating preadipocytes. Changes in promoter structure, histone hyperacetylation, and binding of C/EBP activators, Pol II, and most GTFs preceded the interaction of SWI/SNF enzymes with the PPARgamma2 promoter. However, transcription of the PPARgamma2 gene occurred only upon subsequent association of SWI/SNF and TFIIH with the promoter. Thus, induction of the PPARgamma nuclear hormone receptor during adipogenesis requires SWI/SNF enzymes to facilitate preinitiation complex function.
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PMID:Temporal recruitment of transcription factors and SWI/SNF chromatin-remodeling enzymes during adipogenic induction of the peroxisome proliferator-activated receptor gamma nuclear hormone receptor. 1514 61

The 26S proteasome, consisting of the 20S core and 19S regulatory complexes, regulates intracellular protein concentration through proteolytic degradation of targeted substrates. Composition of the 19S regulatory complex as well as posttranslational modifications of the 19S subunits can effectively regulate the activity of the 26S proteasome. Aberrant activity of the 26S proteasome affects the cell cycle, apoptosis and other cellular processes related to cancer. Recent data show an additional proteasome-independent role of 19S subunits in transcriptional regulation. S12 (Rpn8), the human homologue of mouse Mov-34, is a non-ATPase 19S regulatory subunit of the 26S proteasome. Previous studies have identified phosphorylated S12. In our study, we identify a modified S12 isoform (S12-M) with distinct biochemical properties. The S12-M isoform was found in 6 normal, but not 4 transformed, breast epithelial cell lines. Modification of S12 protein can be induced in vitro by addition of the proteasome inhibitor PSI. Modified and unmodified S12 have similar mass, but different isoelectric points, consistent with phosphorylation. In normal cells, unmodified S12 associates with the 26S proteasome, while modified S12-M does not. Whereas transformed cell line nuclei contain neither S12 isoform, S12-M is predominantly cytosolic in normal cells, with the unmodified S12 present in both the nuclei and cytosol. Together with the role of 19S subunits in transcriptional regulation, homology between S12 and eIF3 and TFIIH subunits, coelution with immunoproteasome subunits, and differential posttranslational modification and nuclear localization, these data suggest a differential nuclear function of modified and unmodified S12 in cancer.
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PMID:Post-translationally modified S12, absent in transformed breast epithelial cells, is not associated with the 26S proteasome and is induced by proteasome inhibitor. 1522 60

TFIIE and TFIIH are essential for the promoter opening and escape that occurs as RNA polymerase II transits into early elongation. XPB, a subunit of TFIIH, contains an ATP-dependent helicase activity that is used in both of these processes. Here, we show that the smaller beta subunit of TFIIE stimulates the XPB helicase and ATPase activities. The larger alpha subunit can use its known inhibitory activity to moderate the stimulation by the beta subunit. Regions of TFIIE beta required for the helicase stimulation were identified. Mutants were constructed that are defective in stimulating the XPB helicase but still allow intact TFIIE to bind and recruit XPB and TFIIH to form the pre-initiation complex. In a test for the functional significance of the stimulatory effect of TFIIE beta, these mutant forms of TFIIE were shown to be defective in a transcription assay on linear DNA. The data suggest that the beta subunit of TFIIE is an ATPase and helicase co-factor that can assist the XPB subunit of TFIIH during transcription initiation and the transition to early elongation, enhancing the potential diversity of regulatory targets.
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PMID:Stimulation of the XPB ATP-dependent helicase by the beta subunit of TFIIE. 1591 39

Loss of a nonenzymatic function of XPG results in defective transcription-coupled repair (TCR), Cockayne syndrome (CS), and early death, but the molecular basis for these phenotypes is unknown. Mutation of CSB, CSA, or the TFIIH helicases XPB and XPD can also cause defective TCR and CS. We show that XPG interacts with elongating RNA polymerase II (RNAPII) in the cell and binds stalled RNAPII ternary complexes in vitro both independently and cooperatively with CSB. XPG binds transcription-sized DNA bubbles through two domains not required for incision and functionally interacts with CSB on these bubbles to stimulate its ATPase activity. Bound RNAPII blocks bubble incision by XPG, but an ATP hydrolysis-dependent process involving TFIIH creates access to the junction, allowing incision. Together, these results implicate coordinated recognition of stalled transcription by XPG and CSB in TCR initiation and suggest that TFIIH-dependent remodeling of stalled RNAPII without release may be sufficient to allow repair.
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PMID:Recognition of RNA polymerase II and transcription bubbles by XPG, CSB, and TFIIH: insights for transcription-coupled repair and Cockayne Syndrome. 1624 22

How subunits of the transcription/repair factor TFIIH cooperate to allow for the removal of DNA lesions or for the transcription of genes is crucial to understand the functioning of this complex. Here, we reveal that p8/TTD-A, the tenth subunit of TFIIH, has a critical role in DNA repair where it triggers DNA opening by stimulating XPB ATPase activity together with the damage recognition factor XPC-hHR23B. Fluorescent antibody labeling shows that such opening is needed for the recruitment of XPA to the site of the damage. By contrast, p8 is dispensable for RNA synthesis and doesn't interfere with the transcriptional function of CAK, although both interact with the XPD subunit. Interestingly, p8 overexpression in TTD-XPD cells counteracts the detrimental effect of XPD mutations by restoring the cellular TFIIH concentration. These findings resolve the primary functions of p8 and unveil how TFIIH components specifically direct the complex toward repair or transcription.
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PMID:p8/TTD-A as a repair-specific TFIIH subunit. 1642 11

The transcription and DNA repair factor TFIIH is composed of 10 subunits. Mutations in the XPB, XPD, and p8 subunits are genetically linked to human diseases, including cancer. However, no reports of mutations in other TFIIH subunits have been reported in higher eukaryotes. Here, we analyze at genetic, molecular, and biochemical levels the Drosophila melanogaster p52 (DMP52) subunit of TFIIH. We found that DMP52 is encoded by the gene marionette in Drosophila and that a defective DMP52 produces UV light-sensitive flies and specific phenotypes during development: organisms are smaller than their wild-type siblings and present tumors and chromosomal instability. The human homologue of DMP52 partially rescues some of these phenotypes. Some of the defects observed in the fly caused by mutations in DMP52 generate trichothiodystrophy and cancer-like phenotypes. Biochemical analysis of DMP52 point mutations introduced in human p52 at positions homologous to those of defects in DMP52 destabilize the interaction between p52 and XPB, another TFIIH subunit, thus compromising the assembly of the complex. This study significantly extends the role of p52 in regulating XPB ATPase activity and, consequently, both its transcriptional and nucleotide excision repair functions.
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PMID:DNA repair and transcriptional deficiencies caused by mutations in the Drosophila p52 subunit of TFIIH generate developmental defects and chromosome fragility. 1733 30


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