Transcription-Austin最新文献

{"title":"Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium.","authors":"Arno L Greenleaf","doi":"10.1080/21541264.2018.1535211","DOIUrl":"10.1080/21541264.2018.1535211","url":null,"abstract":"<p><p>As the new millennium began, CDK12 and CDK13 were discovered as nucleotide sequences that encode protein kinases related to cell cycle CDKs. By the end of the first decade both proteins had been qualified as CTD kinases, and it was emerging that both are heterodimers containing a Cyclin K subunit. Since then, many studies on CDK12 have shown that, through phosphorylating the CTD of transcribing RNAPII, it plays critical roles in several stages of gene expression, notably RNA processing; it is also crucial for maintaining genome stability. Fewer studies on CKD13 have clearly shown that it is functionally distinct from CDK12. CDK13 is important for proper expression of a number of genes, but it also probably plays yet-to-be-discovered roles in other processes. This review summarizes much of the work on CDK12 and CDK13 and attempts to evaluate the results and place them in context. Our understanding of these two enzymes has begun to mature, but we still have much to learn about both. An indicator of one major area of medically-relevant future research comes from the discovery that CDK12 is a tumor suppressor, notably for certain ovarian and prostate cancers. A challenge for the future is to understand CDK12 and CDK13 well enough to explain how their loss promotes cancer development and how we can intercede to prevent or treat those cancers. Abbreviations: CDK: cyclin-dependent kinase; CTD: C-terminal repeat domain of POLR2A; CTDK-I: CTD kinase I (yeast); Ctk1: catalytic subunit of CTDK-I; Ctk2: cyclin-like subunit of CTDK-I; PCAP: phosphoCTD-associating protein; POLR2A: largest subunit of RNAPII; SRI domain: Set2-RNAPII Interacting domain.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 2","pages":"91-110"},"PeriodicalIF":3.6,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1535211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36584460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic targeting of transcriptional cyclin-dependent kinases.","authors":"Matthew D Galbraith,&nbsp;Heather Bender,&nbsp;Joaquín M Espinosa","doi":"10.1080/21541264.2018.1539615","DOIUrl":"https://doi.org/10.1080/21541264.2018.1539615","url":null,"abstract":"<p><p>The fact that many cancer types display transcriptional addiction driven by dysregulation of oncogenic enhancers and transcription factors has led to increased interest in a group of protein kinases, known as transcriptional cyclin dependent kinases (tCDKs), as potential therapeutic targets. Despite early reservations about targeting a process that is essential to healthy cell types, there is now evidence that targeting tCDKs could provide enough therapeutic window to be effective in the clinic. Here, we discuss recent developments in this field, with an emphasis on highly-selective inhibitors and the challenges to be addressed before these inhibitors could be used for therapeutic purposes. Abbreviations: CAK: CDK-activating kinase;CDK: cyclin-dependent kinase;CMGC group: CDK-, MAPK-, GSK3-, and CLK-like;CTD: C-terminal repeat domain of the RPB1 subunit of RNA polymerase II;DRB: 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole;mCRPC: metastatic castration-resistant prostate cancer;NSCLC: non-small cell lung cancer;P-TEFb: positive elongation factor b;RNAPII: RNA polymerase II;S2: serine-2 of CTD repeats;S5: serine-5 of CTD repeats;S7: serine-7 of CTD repeats;SEC: super elongation complex;tCDK: transcriptional cyclin-dependent kinase;TNBC: triple-negative breast cancer.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 2","pages":"118-136"},"PeriodicalIF":3.6,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1539615","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36648303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK9: a signaling hub for transcriptional control.","authors":"Curtis W Bacon,&nbsp;Iván D'Orso","doi":"10.1080/21541264.2018.1523668","DOIUrl":"https://doi.org/10.1080/21541264.2018.1523668","url":null,"abstract":"<p><p>Cyclin-dependent kinase 9 (CDK9) is critical for RNA Polymerase II (Pol II) transcription initiation, elongation, and termination in several key biological processes including development, differentiation, and cell fate responses. A broad range of diseases are characterized by CDK9 malfunction, illustrating its importance in maintaining transcriptional homeostasis in basal- and signal-regulated conditions. Here we provide a historical recount of CDK9 discovery and the current models suggesting CDK9 is a central hub necessary for proper execution of different steps in the transcription cycle. Finally, we discuss the current therapeutic strategies to treat CDK9 malfunction in several disease states. Abbreviations: CDK: Cyclin-dependent kinase; Pol II: RNA Polymerase II; PIC: Pre-initiation Complex; TFIIH: Transcription Factor-II H; snoRNA: small nucleolar RNA; CycT: CyclinT1/T2; P-TEFb: Positive Transcription Elongation Factor Complex; snRNP: small nuclear ribonucleo-protein; HEXIM: Hexamethylene Bis-acetamide-inducible Protein 1/2; LARP7: La-related Protein 7; MePCE: Methylphosphate Capping Enzyme; HIV: human immunodeficiency virus; TAT: trans-activator of transcription; TAR: Trans-activation response element; Hsp70: Heat Shock Protein 70; Hsp90/Cdc37: Hsp90- Hsp90 co-chaperone Cdc37; DSIF: DRB Sensitivity Inducing Factor; NELF: Negative Elongation Factor; CPSF: cleavage and polyadenylation-specific factor; CSTF: cleavage-stimulatory factor; eRNA: enhancer RNA; BRD4: Bromodomain-containing protein 4; JMJD6: Jumonji C-domain-containing protein 6; SEC: Super Elongation Complex; ELL: eleven-nineteen Lys-rich leukemia; ENL: eleven-nineteen leukemia; MLL: mixed lineage leukemia; BEC: BRD4-containing Elongation Complex; SEC-L2/L3: SEC-like complexes; KAP1: Kruppel-associated box-protein 1; KEC: KAP1-7SK Elongation Complex; DRB: Dichloro-1-ß-D-Ribofuranosylbenzimidazole; H2Bub1: H2B mono-ubiquitination; KM: KM05382; PP1: Protein Phosphatase 1; CDK9i: CDK9 inhibitor; SHAPE: Selective 2'-hydroxyl acylation analyzed by primer extension; TE: Typical enhancer; SE : Super enhancer.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 2","pages":"57-75"},"PeriodicalIF":3.6,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1523668","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36500036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular dissection of CHARGE syndrome highlights the vulnerability of neural crest cells to problems with alternative splicing and other transcription-related processes.","authors":"Félix-Antoine Bérubé-Simard,&nbsp;Nicolas Pilon","doi":"10.1080/21541264.2018.1521213","DOIUrl":"https://doi.org/10.1080/21541264.2018.1521213","url":null,"abstract":"<p><p>CHARGE syndrome is characterized by co-occurrence of multiple malformations due to abnormal development of neural crest cells. Here, we review the phenotypic and molecular overlap between CHARGE syndrome and similar pathologies, and further discuss the observation that neural crest cells appear especially sensitive to malfunction of the chromatin-transcription-splicing molecular hub.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 1","pages":"21-28"},"PeriodicalIF":3.6,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1521213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36483048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA processing in skeletal muscle biology and disease.","authors":"Emma R Hinkle,&nbsp;Hannah J Wiedner,&nbsp;Adam J Black,&nbsp;Jimena Giudice","doi":"10.1080/21541264.2018.1558677","DOIUrl":"https://doi.org/10.1080/21541264.2018.1558677","url":null,"abstract":"<p><p>RNA processing encompasses the capping, cleavage, polyadenylation and alternative splicing of pre-mRNA. Proper muscle development relies on precise RNA processing, driven by the coordination between RNA-binding proteins. Recently, skeletal muscle biology has been intensely investigated in terms of RNA processing. High throughput studies paired with deletion of RNA-binding proteins have provided a high-level understanding of the molecular mechanisms controlling the regulation of RNA-processing in skeletal muscle. Furthermore, misregulation of RNA processing is implicated in muscle diseases. In this review, we comprehensively summarize recent studies in skeletal muscle that demonstrated: (i) the importance of RNA processing, (ii) the RNA-binding proteins that are involved, and (iii) diseases associated with defects in RNA processing.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 1","pages":"1-20"},"PeriodicalIF":3.6,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1558677","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36790241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Share and share alike: the role of Tra1 from the SAGA and NuA4 coactivator complexes.","authors":"Alan C M Cheung,&nbsp;Luis Miguel Díaz-Santín","doi":"10.1080/21541264.2018.1530936","DOIUrl":"10.1080/21541264.2018.1530936","url":null,"abstract":"<p><p>SAGA and NuA4 are coactivator complexes required for transcription on chromatin. Although they contain different enzymatic and biochemical activities, both contain the large Tra1 subunit. Recent electron microscopy studies have resolved the complete structure of Tra1 and its integration in SAGA/NuA4, providing important insight into Tra1 function.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 1","pages":"37-43"},"PeriodicalIF":3.6,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1530936","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36675030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global role for coactivator complexes in RNA polymerase II transcription.","authors":"Veronique Fischer,&nbsp;Kenny Schumacher,&nbsp;Laszlo Tora,&nbsp;Didier Devys","doi":"10.1080/21541264.2018.1521214","DOIUrl":"https://doi.org/10.1080/21541264.2018.1521214","url":null,"abstract":"<p><p>SAGA and TFIID are related transcription complexes, which were proposed to alternatively deliver TBP at different promoter classes. Recent genome-wide studies in yeast revealed that both complexes are required for the transcription of a vast majority of genes by RNA polymerase II raising new questions about the role of coactivators.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 1","pages":"29-36"},"PeriodicalIF":3.6,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1521214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36557907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA polymerase I activation and hibernation: unique mechanisms for unique genes.","authors":"Carlos Fernández-Tornero","doi":"10.1080/21541264.2017.1416267","DOIUrl":"https://doi.org/10.1080/21541264.2017.1416267","url":null,"abstract":"<p><p>In yeast, transcription of ribosomal DNA (rDNA) by RNA polymerase I (Pol I) is regulated by unique mechanisms acting at the level of the enzyme. Under stress situations such as starvation, Pol I hibernates through dimerization. When growth conditions are restored, dimer disassembly and Rrn3 binding drive enzyme activation and subsequent recruitment to rDNA.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":" ","pages":"248-254"},"PeriodicalIF":3.6,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2017.1416267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35769825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Architecture of the RNA polymerase II elongation complex: new insights into Spt4/5 and Elf1.","authors":"Haruhiko Ehara,&nbsp;Shun-Ichi Sekine","doi":"10.1080/21541264.2018.1454817","DOIUrl":"https://doi.org/10.1080/21541264.2018.1454817","url":null,"abstract":"<p><p>Transcription by RNA polymerase II (Pol II) is accomplished with the aid of numerous accessory factors specific to each transcriptional stage. The structure of the Pol II elongation complex (EC) bound with Spt4/5, Elf1, and TFIIS unveiled the sophisticated basal EC architecture essential for transcription elongation and other transcription-related events.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"9 5","pages":"286-291"},"PeriodicalIF":3.6,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1454817","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35982700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hinge action versus grip in translocation by RNA polymerase.","authors":"Yuri A Nedialkov,&nbsp;Kristopher Opron,&nbsp;Hailey L Caudill,&nbsp;Fadi Assaf,&nbsp;Amanda J Anderson,&nbsp;Robert I Cukier,&nbsp;Guowei Wei,&nbsp;Zachary F Burton","doi":"10.1080/21541264.2017.1330179","DOIUrl":"https://doi.org/10.1080/21541264.2017.1330179","url":null,"abstract":"<p><p>Based on molecular dynamics simulations and functional studies, a conformational mechanism is posited for forward translocation by RNA polymerase (RNAP). In a simulation of a ternary elongation complex, the clamp and downstream cleft were observed to close. Hinges within the bridge helix and trigger loop supported generation of translocation force against the RNA-DNA hybrid resulting in opening of the furthest upstream i-8 RNA-DNA bp, establishing conditions for RNAP sliding. The β flap tip helix and the most N-terminal β' Zn finger engage the RNA, indicating a path of RNA threading out of the exit channel. Because the β flap tip connects to the RNAP active site through the β subunit double-Ψ-β-barrel and the associated sandwich barrel hybrid motif (also called the flap domain), the RNAP active site is coupled to the RNA exit channel and to the translocation of RNA-DNA. Using an exonuclease III assay to monitor translocation of RNAP elongation complexes, we show that K⁺ and Mg²⁺ and also an RNA 3'-OH or a 3'-H₂ affect RNAP sliding. Because RNAP grip to template suggests a sticky translocation mechanism, and because grip is enhanced by increasing K⁺ and Mg²⁺concentration, biochemical assays are consistent with a conformational change that drives forward translocation as observed in simulations. Mutational analysis of the bridge helix indicates that 778-GARKGL-783 (Escherichia coli numbering) is a homeostatic hinge that undergoes multiple bends to compensate for complex conformational dynamics during phosphodiester bond formation and translocation.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"9 1","pages":"1-16"},"PeriodicalIF":3.6,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2017.1330179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35357945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}