A5002677870- Cancer-related Molecular Pathways
- RNA modifications and cancer
- DNA Repair Mechanisms
- RNA Research and Splicing
- Genomics and Chromatin Dynamics
- HIV Research and Treatment
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Immune Cell Function and Interaction
- CRISPR and Genetic Engineering
- NF-κB Signaling Pathways
- Pluripotent Stem Cells Research
- Genetic factors in colorectal cancer
- interferon and immune responses
- Cytomegalovirus and herpesvirus research
- Microtubule and mitosis dynamics
- Glycosylation and Glycoproteins Research
- Pharmacogenetics and Drug Metabolism
- Protein purification and stability
- Drug Transport and Resistance Mechanisms
- Virus-based gene therapy research
- Signaling Pathways in Disease
- Complement system in diseases
- Epigenetics and DNA Methylation
Central European Institute of Technology
2012-2024
Central European Institute of Technology – Masaryk University
2012-2024
University of California, San Francisco
2005-2015
Center of Advanced European Studies and Research
2015
Masaryk University
2012
University of Veterinary Sciences Brno
2003
Czech Academy of Sciences, Institute of Microbiology
2003
Various cyclin-dependent kinase (Cdk) complexes have been implicated in the regulation of transcription. In this study, we identified a 70-kDa Cyclin K (CycK) that binds Cdk12 and Cdk13 to form two different (CycK/Cdk12 or CycK/Cdk13) human cells. The CycK/Cdk12 complex regulates phosphorylation Ser2 C-terminal domain RNA polymerase II expression small subset genes, as revealed microarrays. Depletion results decreased predominantly long genes with high numbers exons. most prominent group...
Phosphorylation of the RNA polymerase II C-terminal domain (CTD) by cyclin-dependent kinases is important for productive transcription. Here we determine crystal structure Cdk12/CycK and analyse its requirements substrate recognition. Active arranged in an open conformation similar to that Cdk9/CycT but different from those cell cycle kinases. Cdk12 contains a extension folds onto N- lobes thereby contacting ATP ribose. The interaction mediated HE motif followed polybasic cluster conserved...
Cyclin-dependent kinases regulate the cell cycle and transcription in higher eukaryotes. We have determined crystal structure of kinase Cdk13 its Cyclin K subunit at 2.0 Å resolution. contains a C-terminal extension helix composed polybasic cluster DCHEL motif that interacts with bound ATP. Cdk13/CycK phosphorylates both Ser5 Ser2 RNA polymerase II domain (CTD) preference for Ser7 pre-phosphorylations position. The peptidyl-prolyl isomerase Pin1 does not change phosphorylation specificities...
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....
Article25 July 2019Open Access Source DataTransparent process CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes Anil Paul Chirackal Manavalan orcid.org/0000-0002-2113-0715 Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic Search for more papers this author Kveta Pilarova Michael Kluge Institut für Informatik, Ludwig-Maximilians-Universität München, Germany Koen Bartholomeeusen Michal Rajecky Jan Oppelt...
The cyclin-dependent kinases (Cdks) regulate many cellular processes, including the cell cycle, neuronal development, transcription, and posttranscriptional processing. To perform their functions, Cdks bind to specific cyclin subunits form a functional active cyclin/Cdk complex. This review is focused on Cyclin K, which was originally considered an alternative subunit of Cdk9, its newly identified partners, Cdk12 Cdk13. We briefly summarize research devoted each these proteins. also discuss...
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...
Cytochrome P450 1B1 (CYP1B1) is an enzyme that has a unique tumor-specific pattern of expression and capable bioactivating wide range carcinogenic compounds. We have reported previously coordinated upregulation CYP1B1 by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) the aryl hydrocarbon receptor ligands, may increase bioactivation promutagens, benzo[a]pyrene (BaP) in epithelial cells. Here, we extend those studies describing novel mechanism participating regulation...
Transcriptional elongation of most eukaryotic genes by RNA polymerase II requires the kinase activity positive transcription factor b (P-TEFb). The catalytically active P-TEFb complex becomes inactive when sequestered into large cooperative actions 7SK snRNA and HEXIM1. In this study, we report that HEXIM1 forms oligomers in cells. This oligomerization is mediated its predicted coiled-coil region C-terminal domain binds a basic within central part Alanine-mutagenesis evolutionary conserved...
The positive transcription elongation factor b (P-TEFb) is essential for the of and cotranscriptional processing by RNA polymerase II. In mammals, it contains predominantly C-type cyclin T1 (CycT1) or CycT2 cyclin-dependent kinase 9 (Cdk9). To determine if these cyclins have redundant functions affect distinct sets genes, we genetically inactivated gene (Ccnt2) using β-galactosidase-neomycin (β-geo) trap technology in mouse. Visualizing β-galactosidase during mouse embryogenesis revealed...
Abstract Cyclin-dependent kinase 12 (CDK12) phosphorylates the C-terminal domain of RNA polymerase II and is needed for optimal transcription elongation translation a subset human protein-coding genes. The has pleiotropic effect on maintenance genome stability, its inactivation in prostate ovarian tumours results focal tandem duplications, CDK12-unique instability phenotype. CDK12 aberrations were found many other malignancies have potential to be used as biomarkers therapeutic intervention....
The class II transactivator (CIITA) is the master integrator of expression MHC genes. It interacts with variety basal transcription factors to initiate and elongate these Among others, it recruits positive elongation factor b (P-TEFb) promoters. In cells, P-TEFb found in small active or large inactive complexes. complex composed P-TEFb, 7SK nuclear RNA, hexamethylene bisacetamide-inducible protein 1 (Hexim1). present study identifies Hexim1 as a potent inhibitor CIITA-mediated transcription....
A CD8+ cell non-cytotoxic antiviral response (CNAR), mediated by a factor (CAF), is associated with long-term healthy state in human immunodeficiency virus (HIV) infection. CNAR/CAF reduces viral transcription without known effect on specific sequences the HIV genome. In studies to define mechanism involved block transcription, we now report that from HIV-LTR reporter reduced infected CD4+ cells upon treatment CAF. agreement this observation, amount of RNA polymerase II (RNAPII) promoter and...
Abstract The Cdk12/CycK complex promotes gene expression by phosphorylating the C-terminal domain of RNA polymerase II. In previous work we found that CDK12/CycK maintains genomic stability via regulation several key DNA damage response genes such as BRCA1, ATR, FANCD2 or FANCI. CDK12 is among only nine with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, influence these on and their link to cancerogenesis remain ill-defined. Here, show most interfere formation,...