ArticleNucleic acids research2019
The CDK7 inhibitor THZ1 alters RNA polymerase dynamics at the 5' and 3' ends of genes.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Genome-Wide CRISPR/Cas9 Screening Identifies Modulators of THZ1 Response in Acute Myeloid Leukemia.Biomedicines · 2026Article
- Targeting CDK2 and other novel cell cycle targets for breast cancer therapy.Expert opinion on therapeutic targets · 2025Review
- Mutant FOXO1 controls an oncogenic network via enhancer accessibility.Cell genomics · 2024Article
- Super enhancer lncRNAs: a novel hallmark in cancer.Cell communication and signaling : CCS · 2024Review
- Live-cell imaging of endogenous CSB-mScarletI as a sensitive marker for DNA-damage-induced transcription stress.Cell reports methods · 2024Article
- Break-induced RNA-DNA hybrids (BIRDHs) in homologous recombination: friend or foe?EMBO reports · 2023Review
- Novel covalent CDK7 inhibitor potently induces apoptosis in acute myeloid leukemia and synergizes with Venetoclax.Journal of experimental & clinical cancer research : CR · 2023Article
- Human SMARCA5 is continuously required to maintain nucleosome spacing.Molecular cell · 2023Article
- Emerging approaches to CDK inhibitor development, a structural perspective.RSC chemical biology · 2023Article
- PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII.Molecular cell · 2023Article
- Mechanisms of myeloid leukemogenesis: Current perspectives and therapeutic objectives.Blood reviews · 2023Review
- THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours.Cell communication and signaling : CCS · 2022Article
- Review
- HSV-1 and influenza infection induce linear and circular splicing of the long NEAT1 isoform.PloS one · 2022Article
- Gene Transcription as a Therapeutic Target in Leukemia.International journal of molecular sciences · 2021Review
- Review
- Definition of a small core transcriptional circuit regulated by AML1-ETO.Molecular cell · 2021Article
- Profiling of 3D Genome Organization in Nasopharyngeal Cancer Needle Biopsy Patient Samples by a Modified Hi-C Approach.Frontiers in genetics · 2021Article
- Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.EMBO molecular medicine · 2020Article
- Epigenetic reprogramming and chromatin accessibility in pediatric diffuse intrinsic pontine gliomas: a neural developmental disease.Neuro-oncology · 2020Review
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Authors and funding
8 authors.
Funding
Abstract
The t(8;21) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). We found that t(8;21) AML were extremely sensitive to THZ1, which triggered apoptosis after only 4 h. We used precision nuclear run-on transcription sequencing (PROseq) to define the global effects of THZ1 and other CDK inhibitors on RNA polymerase II dynamics. Inhibition of CDK7 using THZ1 caused wide-spread loss of promoter-proximal paused RNA polymerase. This loss of 5' pausing was associated with accumulation of polymerases in the body of a large number of genes. However, there were modest effects on genes regulated by 'super-enhancers'. At the 3' ends of genes, treatment with THZ1 suppressed RNA polymerase 'read through' at the end of the last exon, which resembled a phenotype associated with a mutant RNA polymerase with slower elongation rates. Consistent with this hypothesis, polyA site-sequencing (PolyA-seq) did not detect differences in poly A sites after THZ1 treatment. PROseq analysis after short treatments with THZ1 suggested that these 3' effects were due to altered CDK7 activity at the 5' end of long genes, and were likely to be due to slower rates of elongation.
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