Transcription-Austin最新文献

{"title":"Transcriptional CDKs in the spotlight.","authors":"Joaquin M Espinosa","doi":"10.1080/21541264.2019.1597479","DOIUrl":"https://doi.org/10.1080/21541264.2019.1597479","url":null,"abstract":"At every active gene in any genome, there is a transcription cycle, defined as the collective set of biochemical reactions that control RNA polymerase activity, from promoter binding to polymerase recycling. The transcription cycle serves as a command center where multiple sources of information are integrated to ensure that RNA synthesis across genomic loci is tailored precisely to the needs of the cell and organism. Despite its critical importance, our understanding of the transcription cycle is limited, and this lack of knowledge hampers our ability to manipulate transcriptional activity for myriad purposes, both in basic research and the applied sciences. Within this framework, in this issue of Transcription, we are excited to publish a series of reviews focused on key regulators of the transcription cycle: the transcriptional cyclindependent kinases or tCDKs. CDKs are a distinct class of serine-threonine protein kinases that share a core set of features, including the requirement of a cyclin partner and phosphorylation of their ‘activating T-loops’ by a CDK-activating kinase (CAK). In vertebrates, a distinct set of CDKs have clear roles in the regulation of cell cycle progression (CDK1, −2, −4, −6), while a different subset is involved mostly in transcriptional control (tCDKs: CDK7, −8, −9, −12, −13, −19) (ref 1–3). Our understanding of tCDKs has evolved rapidly in the last decade, yet for some of these proteins, our knowledge is still minimal, as in the cases of CDK12, CDK13, and CDK19. Even for the more well-studied tCDKs, such as CDK7 and CDK9, recent discoveries have changed our view of their mechanism of action and their roles in cell biology. Thus, we felt at Transcription that the time was right to have an updated view of the field, with a focus on recent discoveries and future venues for research. The need for these reviews is further justified by the increasing recognition that tCDKs could be valid targets of pharmacological intervention for the management of a number of human pathologies. In this issue of Transcription, Robert Fisher gets us started with an entertaining and thorough update on the state of affairs for CDK7, arguably the most multifaceted of the tCDKs, describing unanticipated roles for this enzyme in capping, termination, and polymerase recycling, while also sharing promising news about the therapeutic value of CDK7 inhibitors [4]. Then, Bacon and D’Orso bring us up to speed on CDK9, which they accurately describe as a “signaling hub” for transcriptional control, providing detailed descriptions of the mechanisms regulating CDK9 activity, as well as the roles of CDK9 in gene and enhancer transcription, RNA processing, chromatin regulation, and its roles in human disease [5]. Next, Fant and Taatjes provide an expert testimony about the Mediator-associated kinases, CDK8 and CDK19, introducing new and intriguing roles in enhancer-promoter communication, transcriptional memory, metabolism, and, in the case of CDK19, kina","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 2","pages":"45-46"},"PeriodicalIF":3.6,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2019.1597479","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37120021","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":"Regulatory functions of the Mediator kinases CDK8 and CDK19.","authors":"Charli B Fant,&nbsp;Dylan J Taatjes","doi":"10.1080/21541264.2018.1556915","DOIUrl":"https://doi.org/10.1080/21541264.2018.1556915","url":null,"abstract":"<p><p>The Mediator-associated kinases CDK8 and CDK19 function in the context of three additional proteins: CCNC and MED12, which activate CDK8/CDK19 kinase function, and MED13, which enables their association with the Mediator complex. The Mediator kinases affect RNA polymerase II (pol II) transcription indirectly, through phosphorylation of transcription factors and by controlling Mediator structure and function. In this review, we discuss cellular roles of the Mediator kinases and mechanisms that enable their biological functions. We focus on sequence-specific, DNA-binding transcription factors and other Mediator kinase substrates, and how CDK8 or CDK19 may enable metabolic and transcriptional reprogramming through enhancers and chromatin looping. We also summarize Mediator kinase inhibitors and their therapeutic potential. Throughout, we note conserved and divergent functions between yeast and mammalian CDK8, and highlight many aspects of kinase module function that remain enigmatic, ranging from potential roles in pol II promoter-proximal pausing to liquid-liquid phase separation.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 2","pages":"76-90"},"PeriodicalIF":3.6,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1556915","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36813218","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":"Roles of CDKs in RNA polymerase II transcription of the HIV-1 genome.","authors":"Andrew P Rice","doi":"10.1080/21541264.2018.1542254","DOIUrl":"https://doi.org/10.1080/21541264.2018.1542254","url":null,"abstract":"<p><p>Studies of RNA Polymerase II (Pol II) transcription of the HIV-1 genome are of clinical interest, as the insight gained may lead to strategies to selectively reactivate latent viruses in patients in whom viral replication is suppressed by antiviral drugs. Such a targeted reactivation may contribute to a functional cure of infection. This review discusses five Cyclin-dependent kinases - CDK7, CDK9, CDK11, CDK2, and CDK8 - involved in transcription and processing of HIV-1 RNA. CDK7 is required for Pol II promoter clearance of reactivated viruses; CDK7 also functions as an activating kinase for CDK9 when resting CD4⁺ T cells harboring latent HIV-1 are activated. CDK9 is targeted by the viral Tat protein and is essential for productive Pol II elongation of the HIV-1 genome. CDK11 is associated with the TREX/THOC complex and it functions in the 3' end processing and polyadenylation of HIV-1 transcripts. CDK2 phosphorylates Tat and CDK9 and this stimulates Tat activation of Pol II transcription. CDK8 may stimulate Pol II transcription of the HIV-1 genome through co-recruitment with NF-κB to the viral promoter. Some notable open questions are discussed concerning the roles of these CDKs in HIV-1 replication and viral latency.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 2","pages":"111-117"},"PeriodicalIF":3.6,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541264.2018.1542254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36675028","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":"Cdk7: a kinase at the core of transcription and in the crosshairs of cancer drug discovery.","authors":"Robert P Fisher","doi":"10.1080/21541264.2018.1553483","DOIUrl":"10.1080/21541264.2018.1553483","url":null,"abstract":"<p><p>The transcription cycle of RNA polymerase II (Pol II) is regulated by a set of cyclin-dependent kinases (CDKs). Cdk7, associated with the transcription initiation factor TFIIH, is both an effector CDK that phosphorylates Pol II and other targets within the transcriptional machinery, and a CDK-activating kinase (CAK) for at least one other essential CDK involved in transcription. Recent studies have illuminated Cdk7 functions that are executed throughout the Pol II transcription cycle, from promoter clearance and promoter-proximal pausing, to co-transcriptional chromatin modification in gene bodies, to mRNA 3´-end formation and termination. Cdk7 has also emerged as a target of small-molecule inhibitors that show promise in the treatment of cancer and inflammation. The challenges now are to identify the relevant targets of Cdk7 at each step of the transcription cycle, and to understand how heightened dependence on an essential CDK emerges in cancer, and might be exploited therapeutically.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"10 2","pages":"47-56"},"PeriodicalIF":3.6,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602562/pdf/ktrn-10-02-1553483.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36716578","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":"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}