Transcription by RNA polymerase II (pol II) is regulated by kinases. In recent years, many selective and potent inhibitors of pol II transcription-associated kinases have been developed, and these molecules have advanced understanding of kinase function in mammalian cells. Here, we focus on chemical inhibitors of the transcription-associated kinases CDK7, CDK8, CDK9, CDK12, CDK13, and CDK19. We provide a brief overview of the function of these kinases and common activation mechanisms. We then highlight the advantages of kinase inhibitors compared with other basic research methods, and describe the caveats associated with non-selective compounds (e.g. flavopiridol). We conclude with strategies and recommendations for implementation of chemical inhibitors for experimental analysis of transcription-associated kinases.
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http://dx.doi.org/10.1016/j.cbpa.2022.102186 | DOI Listing |
Sci Rep
August 2024
Hospital Campus Laboratory, Radioisotope Center, Central Institute of Radioisotope Science and Safety Management, Kyushu University, Fukuoka, 812-8582, Japan.
Although previous studies have reported that pre-mRNA splicing factors (SFs) are involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), their exact role in promoting HR remains poorly understood. Here, we showed that SART1, an SF upregulated in several types of cancer, promotes DSB end resection, an essential first step of HR. The resection-promoting function of SART1 requires phosphorylation at threonine 430 and 695 by ATM/ATR.
View Article and Find Full Text PDFMol Genet Genomics
May 2024
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, 41092, Seville, Spain.
RECQL5 is a member of the conserved RecQ family of DNA helicases involved in the maintenance of genome stability that is specifically found in higher eukaryotes and associates with the elongating RNA polymerase II. To expand our understanding of its function we expressed human RECQL5 in the yeast Saccharomyces cerevisiae, which does not have a RECQL5 ortholog. We found that RECQL5 expression leads to cell growth inhibition, increased genotoxic sensitivity and transcription-associated hyperrecombination.
View Article and Find Full Text PDFGene
September 2024
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China. Electronic address:
Long noncoding RNAs (lncRNAs) are implicated in a number of regulatory functions in eukaryotic genomes. In humans, KCNQ1OT1 is a 91 kb imprinted lncRNA that inhibits multiple surrounding genes in cis. Among them, CDKN1C is closely related to KCNQ1OT1 and is involved in multiple epigenetic disorders.
View Article and Find Full Text PDFNat Cell Biol
April 2024
Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
Efficient gene expression requires RNA polymerase II (RNAPII) to find chromatin targets precisely in space and time. How RNAPII manages this complex diffusive search in three-dimensional nuclear space remains largely unknown. The disordered carboxy-terminal domain (CTD) of RNAPII, which is essential for recruiting transcription-associated proteins, forms phase-separated droplets in vitro, hinting at a potential role in modulating RNAPII dynamics.
View Article and Find Full Text PDFCell Rep
March 2024
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:
The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with the expression level and guanine-cytosine (GC) content of transcribed genes. In human neuron-like cells in culture, we map locations of poly(ADP-ribose) and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content.
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