FarUpStream Element (FUSE) Binding Protein (FBP) binds the human c-myc FUSE in vitro only in single-stranded or supercoiled DNA. Because transcriptionally generated torsion melts FUSE in vitro even in linear DNA, and FBP/ FBP Interacting Repressor (FIR) regulates transcription through TFIIH, these components have been speculated to be the mechanosensor (FUSE) and effectors (FBP/FIR) of a real-time mechanism controlling c-myc transcription. To ascertain whether the FUSE/FBP/FIR system operates according to this hypothesis in vivo, the flux of activators, repressors and chromatin remodeling complexes on the c-myc promoter was monitored throughout the seruminduced pulse of transcription. After transcription was switched on by conventional factors and chromatin regulators, FBP and FIR were recruited and established a dynamically remodeled loop with TFIIH at the P2 promoter. In XPB cells carrying mutant TFIIH, loop formation failed and the serum response was abnormal; RNAi depletion of FIR similarly disabled c-myc regulation. Engineering FUSE into episomal vectors predictably re-programmed metallothionein-promoter-driven reporter expression. The in vitro recruitment of FBP and FIR to dynamically stressed c-myc DNA paralleled the in vivo process.
The torsional stress caused by counter-rotation of the transcription machinery and template generates supercoils in a closed topological domain, but has been presumed to be too short-lived to be significant in an open domain. This report shows that transcribing RNA polymerases dynamically sustain sufficient torsion to perturb DNA structure even on linear templates. Assays to capture and measure transcriptionally generated torque and to trap short-lived perturbations in DNA structure and conformation showed that the transient forces upstream of active promoters are large enough to drive the supercoil-sensitive far upstream element (FUSE) of the human c-myc into single-stranded DNA. An alternative non-B conformation of FUSE found in stably supercoiled DNA is not accessible dynamically. These results demonstrate that dynamic disturbance of DNA structure provides a real-time measure of ongoing genetic activity.
With recent advances in computing technology, massive amounts of data and information are being constantly accumulated. Especially in the field of finance, we have great opportunities to create useful insights by analyzing that information, because the financial market produces a tremendous amount of real-time data, including transaction records. Accordingly, this study intends to develop a novel stock market prediction model using the available financial data. We adopt deep learning technique because of its excellent learning ability from the massive dataset. In this study, we propose a hybrid approach integrating long short-term memory (LSTM) network and genetic algorithm (GA). Heretofore, trial and error based on heuristics is commonly used to estimate the time window size and architectural factors of LSTM network. This research investigates the temporal property of stock market data by suggesting a systematic method to determine the time window size and topology for the LSTM network using GA. To evaluate the proposed hybrid approach, we have chosen daily Korea Stock Price Index (KOSPI) data. The experimental result demonstrates that the hybrid model of LSTM network and GA outperforms the benchmark model.
c-myc and p53 networks control proliferation, differentiation, and apoptosis and are responsive to, and cross-regulate a variety of stresses and metabolic and biosynthetic processes. At c-myc, the far upstream element binding protein (FBP) and FBP-interacting repressor (FIR) program transcription by looping to RNA polymerase II complexes engaged at the promoter. Another FBP partner, JTV1/AIMP2, a structural subunit of a multi-aminoacyl-tRNA synthetase (ARS) complex, has also been reported to stabilize p53 via an apparently independent mechanism. Here, we show that in response to oxidative stress, JTV1 dissociates from the ARS complex, translocates to the nucleus, associates with FBP and co-activates the transcription of a new FBP target, ubiquitin-specific peptidase 29 (USP29). A previously uncharacterized deubiquitinating enzyme, USP29 binds to, cleaves poly-ubiquitin chains from, and stabilizes p53. The accumulated p53 quickly induces apoptosis. Thus, FBP and JTV1 help to coordinate the molecular and cellular response to oxidative stress.
The three far-upstream element (FUSE) binding protein (FBP) family members have been ascribed different functions in gene regulation. They were therefore examined with various biochemical, molecular biological, and cell biological tests to evaluate whether their sequence differences reflect functional customization or neutral changes at unselected residues. Each FBP displayed a characteristic profile of intrinsic transcription activation and repression, binding with protein partners, and subcellular trafficking. Although some differences, such as weakened FBP3 nuclear localization, were predictable from primary sequence differences, the unexpected failure of FBP3 to bind the FBP-interacting repressor (FIR) was traced to seemingly conservative substitutions within a small patch of an N-terminal ␣-helix. The transactivation strength and the FIR-binding strength of the FBPs were in the opposite order. Despite their distinguishing features and differential activities, the FBPs traffic to shared subnuclear sites and regulate many common target genes, including c-myc. Though a variety of functions have been attributed to the FBPs, based upon their panel of shared and unique features, we propose that they constitute a molecular regulatory kit that tunes the expression of shared targets through a common mechanism.The far-upstream element (FUSE) binding protein (FBP) binds the FUSE of the human c-myc proto-oncogene (1, 10, 16, 32). The DNA-binding domain (DBD) of FBP contains four repeated hnRNPK homology (KH) motifs. Though they are commonly called an RNA-binding motif, some KH domain proteins-including hnRNP K, the prototype of this familyengage single-stranded DNA with an affinity and sequence specificity equal to or greater than those of RNA (3,4,10,16,32). The carboxyl-terminal domain of FBP stimulates transcription complexes transiting between initiation and promoter escape via activation of the p89/XPB helicase subunit of TFIIH (29). Transcription activation requires at least one copy of a tyrosine-rich motif that is repeated three times in the carboxylterminal activation domain (AD) (11). The less well characterized amino terminus of FBP impairs the action of some, but not all, transcription activators (for example, FBP itself and E1a but not VP16) (11).FBP function is modified by at least two partner proteins. Recruited by FBP, the amino terminus of the FBP-interacting repressor (FIR) blunts AD-mediated stimulation of the p89/XPB helicase activity, permitting only basal transcription (27). Both FBP activation and FIR repression are blocked by mutations in p89/XPB. Associating with the AD, p38/JTV-1/AIMP2 targets FBP for ubiquitinylation and degradation (22). p38 was originally identified as a core protein of a multi-aminoacyl-tRNA synthetase complex (34,36,38,40), and the knockout of p38 in mice indeed dissociates this complex (21); nevertheless, the knockout pups, which develop to full term, support normal levels of protein synthesis (22). Hyperplasia of the lungs and some other organs cause neonatal lethality....
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