A5031840988- RNA Research and Splicing
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- RNA and protein synthesis mechanisms
- HIV Research and Treatment
- Cancer-related Molecular Pathways
- RNA Interference and Gene Delivery
- Protein Degradation and Inhibitors
- Immune Cell Function and Interaction
- Ubiquitin and proteasome pathways
- interferon and immune responses
- DNA Repair Mechanisms
- HIV/AIDS drug development and treatment
- RNA regulation and disease
- NF-κB Signaling Pathways
- CRISPR and Genetic Engineering
- Cell death mechanisms and regulation
- Viral Infections and Immunology Research
- Virology and Viral Diseases
- Bacteriophages and microbial interactions
- Phagocytosis and Immune Regulation
- Influenza Virus Research Studies
- Immunotherapy and Immune Responses
- Cytokine Signaling Pathways and Interactions
- Immune Response and Inflammation
University of Helsinki
2011-2023
University of California, San Francisco
1999-2012
University of Ljubljana
2001-2003
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
2003
Harvard University
2003
Howard Hughes Medical Institute
1999-2001
Hexamethylene bisacetamide (HMBA) is a potent inducer of cell differentiation and HIV production in chronically infected cells. However, its mechanism action remains poorly defined. In this study, we demonstrate that HMBA activates transiently the PI3K/Akt pathway, which leads to phosphorylation HEXIM1 subsequent release active positive transcription elongation factor b (P-TEFb) from transcriptionally inactive complex with 7SK small nuclear RNA (snRNA). As result, P-TEFb recruited promoter...
Human immunodeficiency virus type 1 (HIV-1) transcriptional transactivator (Tat) recruits the positive transcription elongation factor b (P-TEFb) to viral promoter. Consisting of cyclin dependent kinase 9 (Cdk9) and T1, P-TEFb phosphorylates RNA polymerase II negative stimulate HIV-1 genes. A major fraction nuclear is sequestered into a transcriptionally inactive 7SK small ribonucleoprotein (snRNP) by coordinated actions (snRNA) hexamethylene bisacetamide (HMBA) induced protein (HEXIM1). In...
Eukaryotic gene expression is commonly controlled at the level of RNA polymerase II (RNAPII) pausing subsequent to transcription initiation. Transcription elongation stimulated by positive factor b (P-TEFb) kinase, which suppressed within 7SK small nuclear ribonucleoprotein (7SK snRNP). However, biogenesis and functional significance snRNP remain poorly understood. Here, we report that LARP7, BCDIN3, noncoding (7SK) are vital for formation stability a cell stress-resistant core snRNP. Our...
The Cdk12/CycK complex promotes expression of a subset RNA polymerase II genes, including those the DNA damage response. CDK12 is among only nine genes with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, influence these on and their link to cancerogenesis remain ill-defined. Here, we show that most prevent formation complex, rendering kinase inactive. By examining within structure, find they likely provoke structural rearrangements detrimental Cdk12 activation....
DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill defined. Here, we show that following genotoxic stress, RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating positive elongation factor b (P-TEFb) via its release from inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). This is mediated activation p38MAPK, triggers enhanced binding RBM7 with core...
Promoter-proximal pausing of RNAPII coincides with the formation cap structure at 5' end pre-mRNA, which is bound by cap-binding protein complex (CBC). Although positive transcription elongation factor b (P-TEFb) stimulates release from and promotes alternative splicing phosphorylating C-terminal domain Ser2 (S2-P RNAPII), it unknown whether CBC facilitates these events. In this study, we report that interacts P-TEFb transcriptionally engaged globally required for optimal levels S2-P RNAPII....
The positive transcription elongation factor b (P-TEFb) contains cyclin T1 (CycT1) and cyclin-dependent kinase 9 (Cdk9). For activating the expression of eukaryotic genes, histidine-rich sequence in CycT1 binds heptapeptide repeats C-terminal domain (CTD) RNA polymerase II (RNAPII), whereupon Cdk9 phosphorylates CTD. We found that alanine-substituted cannot be phosphorylated also bind CycT1. When placed near units, these CTD analogs block effects P-TEFb. Remarkably, transcriptional repressor...
The active form of the positive transcription elongation factor b (P-TEFb) consists cyclin T and kinase Cdk9. P-TEFb stimulates by phosphorylating C-terminal domain RNA polymerase II. It becomes inactivated when associated in a tetrameric complex with abundant 7SK small nuclear recently identified protein Hexim1. In this study, we stable soluble (residues 255-359) Hexim1 12.5-kDa size that binds boxes Cyclin T1. Functional assays HeLa cells showed T-binding (TBD) is required for binding to...
Studies of the transcriptional transactivator (Tat), a key regulatory protein HIV, have yielded insight into control eukaryotic transcription.
Hexim1 is a cellular protein that associates with the positive transcription elongation factor b (P-TEFb) to regulate RNA polymerase II of nascent mRNA transcripts. It directly binds Cyclin T1 P-TEFb and inhibits kinase activity Cdk9, leading an arrest elongation. Here, we report solution structure T binding domain (TBD) forms parallel coiled-coil homodimer composed two segments preceding alpha helix folds back onto first unit. NMR titration, fluorescence, immunoprecipitation experiments...
The positive transcription elongation factor b (P-TEFb) regulates RNA polymerase II elongation. In cells, P-TEFb partitions between small active and larger inactive states. the latter, HEXIM1 binds to 7SK snRNA recruits as well inactivates in snRNP. Several stimuli can affect this equilibrium. study, we demonstrate that protein kinase C (PKC) phosphorylates serine at position158 (S158) HEXIM1. This phosphorylated neither nor inhibits P-TEFb. Phorbol esters or engagement of T cell antigen...
Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed combination therapy. We screened comprehensive oncology library and identified clinically relevant antimetabolites Mouse double minute 2 homolog (MDM2) inhibitors top compounds eliciting p53-dependent death...
ABSTRACT Transcriptional transactivators (Tat) from many lentiviruses interact with their cognate transactivation response RNA structures (TAR) to increase rates of elongation rather than initiation transcription. For several them, the complex Tat and a species-specific cyclin T1 must be formed before binding TAR can occur high affinity specificity. In sharp contrast, bovine immunodeficiency virus (BIV) binds its without help T1. This depends on upper stem 5′ bulge, but not central loop in...
By recruiting the positive transcriptional elongation factor b (P-TEFb) to paused RNA polymerase II, transactivator Tat stimulates of human immunodeficiency virus type 1 (HIV-1) genome. We found that cyclin-dependent kinase 9 (Cdk9), catalytic subunit P-TEFb, is ubiquitylated in vivo. This ubiquitylation depended on Skp1/Cul1/F-box protein E3 ubiquitin ligase Skp2. Likewise, required Skp2 since its transactivation HIV-1 long terminal repeat decreased primary mouse embryonic fibroblasts,...
A virus protein called Tat plays a dual role in HIV infection by regulating the expression of genes belonging to and host cells.
P-TEFb and CDK12 facilitate transcriptional elongation by RNA polymerase II. Given the prominence of both kinases in cancer, gaining a better understanding their interplay could inform design novel anti-cancer strategies. While down-regulation DNA repair genes CDK12-targeted cancer cells is being explored therapeutically, little known about mechanisms significance induction upon inhibition CDK12. We show that selective targeting colon cancer-derived activates via its release from inhibitory...