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: UMLS:C0344329 (collapse)
28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied promoter clearance at a series of RNA polymerase II promoters with varying spacing of the TATA box and start site. We find that regardless of promoter spacing, the upstream edge of the transcription bubble forms 20 bp from TATA. The bubble expands downstream until 18 bases are unwound and the RNA is at least 7 nt long, at which point the upstream approximately 8 bases of the bubble abruptly reanneal (bubble collapse). If either bubble size or transcript length is insufficient, bubble collapse cannot occur. Bubble collapse coincides with the end of the requirement for the TFIIH helicase for efficient transcript elongation. We also provide evidence that bubble collapse suppresses pausing at +7 to +9 caused by the presence of the B finger segment of TFIIB within the complex. Our results indicate that bubble collapse defines the RNA polymerase II promoter clearance transition.
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PMID:The role of the transcription bubble and TFIIB in promoter clearance by RNA polymerase II. 1598 68

Elongin A is the transcriptionally active subunit of the Elongin complex that strongly stimulates the rate of elongation by RNA polymerase II (pol II) by suppressing the transient pausing of the polymerase at many sites along the DNA template. We have recently shown that Elongin A-deficient mice are embryonic lethal, and mouse embryonic fibroblasts (MEFs) derived from Elongin A(-/-) embryos display not only increased apoptosis but also senescence-like phenotypes accompanied by the activation of p53. To further understand the function of Elongin A in vivo, we have carried out the structure-function analysis of Elongin A and identified sequences critical to its nuclear localization and direct interaction with pol II. Moreover, we have analyzed the replication fork movement in wild-type and Elongin A(-/-) MEFs, and shown the possibility that the genomic instability observed in Elongin A(-/-) MEFs might be caused by the replication fork collapse due to Elongin A deficiency.
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PMID:Functional characterization of a mammalian transcription factor, Elongin A. 1711 77

Transcript initiation by RNA polymerase II (pol II) requires a helicase within TFIIH to generate the unpaired template strand. However, pol II preinitiation complexes (PICs) lose the ability to synthesize RNA very rapidly upon exposure to ATP alone in the absence of other NTPs. This inactivation is not caused by the TFIIH kinase activity, the loss of transcription factors or pol II from the PIC, or the collapse of the initially formed transcription bubble. TFIIE is necessary for PIC formation, but TFIIE is not retained as a stable component in PICs prepared by our protocol. Nevertheless, activity can be at least partially restored to ATP-treated PICs by the readdition of TFIIE. PICs formed on premelted (bubble) templates require TFIIH for effective transcript elongation to +20. Incubation of bubble template PICs with ATP caused reduced yields of 20-mers, but this effect was partially reversed by the addition of TFIIE. Our results suggest that once the open complex is formed, TFIIH decays into an inactive configuration in the absence of nucleotides for transcription. Although TFIIE does not play a role in transcript initiation itself, inactivation resulting from ATP preincubation can be reversed by a remodeling process mediated by TFIIE. Finally, we have also uncovered a major role for TFIIF in the earliest stages of transcript elongation that is unique to bubble templates.
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PMID:Inactivated RNA polymerase II open complexes can be reactivated with TFIIE. 2211 17

Pausing during the earliest stage of transcript elongation by RNA polymerase II (Pol II) is a nearly universal control point in metazoan gene expression. The substoichiometric Pol II subunit Gdown1 facilitates promoter proximal pausing in vitro in extract-based transcription reactions, out-competes the initiation/elongation factor TFIIF for binding to free Pol II and co-localizes with paused Pol II in vivo. However, we have shown that Gdown1 cannot functionally associate with the Pol II preinitiation complex (PIC), which contains TFIIF. In the present study, we determined at what point after initiation Gdown1 can associate with Pol II and how rapidly this competition with TFIIF occurs. We show that, as with the PIC, Gdown1 cannot functionally load into open complexes or complexes engaged in abortive synthesis of very short RNAs. Gdown1 can load into early elongation complexes (EECs) with 5-9 nt RNAs, but efficient association with EECs does not take place until the point at which the upstream segment of the long initial transcription bubble reanneals. Tests of EECs assembled on a series of promoter variants confirm that this bubble collapse transition, and not transcript length, modulates Gdown1 functional affinity. Gdown1 displaces TFIIF effectively from all complexes downstream of the collapse transition, but this displacement is surprisingly slow: complete loss of TFIIF stimulation of elongation requires 5 min of incubation with Gdown1. The relatively slow functional loading of Gdown1 in the presence of TFIIF suggests that Gdown1 works in promoter-proximal pausing by locking in the paused state after elongation is already antagonized by other factors, including DSIF, NELF and possibly the first downstream nucleosome.
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PMID:Gdown1 Associates Efficiently with RNA Polymerase II after Promoter Clearance and Displaces TFIIF during Transcript Elongation. 2771 20

Mutations that attenuate homologous recombination (HR)-mediated repair promote tumorigenesis and sensitize cells to chemotherapeutics that cause replication fork collapse, a phenotype known as 'BRCAness'¹. BRCAness tumours arise from loss-of-function mutations in 22 genes¹. Of these genes, all but one (CDK12) function directly in the HR repair pathway¹. CDK12 phosphorylates serine 2 of the RNA polymerase II C-terminal domain heptapeptide repeat^2-7, a modification that regulates transcription elongation, splicing, and cleavage and polyadenylation^8,9. Genome-wide expression studies suggest that depletion of CDK12 abrogates the expression of several HR genes relatively specifically, thereby blunting HR repair^3-7,10,11. This observation suggests that the mutational status of CDK12 may predict sensitivity to targeted treatments against BRCAness, such as PARP1 inhibitors, and that CDK12 inhibitors may induce sensitization of HR-competent tumours to these treatments^6,7,10,11. Despite growing clinical interest, the mechanism by which CDK12 regulates HR genes remains unknown. Here we show that CDK12 globally suppresses intronic polyadenylation events in mouse embryonic stem cells, enabling the production of full-length gene products. Many HR genes harbour more intronic polyadenylation sites than other expressed genes, and these sites are particularly sensitive to loss of CDK12. The cumulative effect of these sites accounts for the enhanced sensitivity of HR gene expression to CDK12 loss, and we find that this mechanism is conserved in human tumours that contain loss-of-function CDK12 mutations. This work clarifies the function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumour biomarker.
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PMID:CDK12 regulates DNA repair genes by suppressing intronic polyadenylation. 3092 Aug 4

Delineating how chromosomes fold at length scales beyond one megabase remains obscure relative to smaller-scale folding into TADs, loops, and nucleosomes. We find that rather than simply unfolding chromatin, histone hyperacetylation results in interactions between distant genomic loci separated by tens to hundreds of megabases, even in the absence of transcription. These hyperacetylated "megadomains" are formed by the BRD4-NUT fusion oncoprotein, interact both within and between chromosomes, and form a specific nuclear subcompartment that has elevated gene activity with respect to other subcompartments. Pharmacological degradation of BRD4-NUT results in collapse of megadomains and attenuation of the interactions between them. In contrast, these interactions persist and contacts between newly acetylated regions are formed after inhibiting RNA polymerase II initiation. Our structure-function approach thus reveals that broad chromatin domains of identical biochemical composition, independent of transcription, form nuclear subcompartments, and also indicates the potential of altering chromosome structure for treating human disease.
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PMID:Chromatin Hyperacetylation Impacts Chromosome Folding by Forming a Nuclear Subcompartment. 3228 35

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