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The CDK7 Inhibitor THZ1 Alters RNA Polymerase Dynamics at the 5 ' and 3 ' Ends of Genes

dc.contributor.authorSampathi, Shilpa
dc.contributor.authorAcharya, Pankaj
dc.contributor.authorZhao, Yue
dc.contributor.authorWang, Jing
dc.contributor.authorStengel, Kristy
dc.contributor.authorLiu, Qi
dc.contributor.authorSavona, Michael R.
dc.contributor.authorHiebert, Scott W.
dc.identifier.citationShilpa Sampathi, Pankaj Acharya, Yue Zhao, Jing Wang, Kristy R Stengel, Qi Liu, Michael R Savona, Scott W Hiebert, The CDK7 inhibitor THZ1 alters RNA polymerase dynamics at the 5′ and 3′ ends of genes, Nucleic Acids Research, Volume 47, Issue 8, 07 May 2019, Pages 3921–3936,
dc.description.abstractThe 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.en_US
dc.description.sponsorshipNational Cancer Institute (NIH) [CA178030, CA64140]. Funding for open access charge: NIH [CA64140].en_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You are not required to obtain permission to reuse this article.
dc.subjecttranscription elongationen_US
dc.subjectoncogenic transcriptionen_US
dc.subjectprocessing machineryen_US
dc.subjectT(8/21) AMLen_US
dc.subjectcarboxy-terminal domainen_US
dc.subject.lcshMyeloid leukemiaen_US
dc.titleThe CDK7 Inhibitor THZ1 Alters RNA Polymerase Dynamics at the 5 ' and 3 ' Ends of Genesen_US

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