@article{b7ba6b28ef6d43d3b1a85cf247a6ceaa,
title = "The CDK7 inhibitor THZ1 alters RNA polymerase dynamics at the 5' and 3' ends of genes",
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 'superenhancers'. 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.",
author = "Shilpa Sampathi and Pankaj Acharya and Yue Zhao and Jing Wang and Stengel, {Kristy R.} and Qi Liu and Savona, {Michael R.} and Hiebert, {Scott W.}",
note = "Funding Information: National Cancer Institute (NIH) [CA178030, CA64140]. Funding for open access charge: NIH [CA64140]. Conflict of interest statement. Research Funding from In-cyte. Funding Information: We thank all the members of Hiebert lab for helpful discussions, reagents and advice. This work was supported by NIH grant 1S10RR028106-01A1 for the Next Generation Nucleic Acid Sequencer, housed in Vanderbilt Technologies for Advanced Genomics (VANTAGE). We thank the Flow Cytometry and VANTAGE shared resources for services and support. AML patient samples were collected under an IRB approved protocol through the Hematologic Malignancies Tumor Bank, a Vanderbilt-Ingram Cancer Center supported resource. This work was supported by the T.J. Martell Foundation, the Robert J. Kleberg, Jr and Helen C. Kleberg Foundation, National Institutes of Health grants (RO1-CA109355, RO1-CA164605 and R01-CA64140 to S.W.H.) and core services performed through Vanderbilt Digestive Disease Research grant (NIDDK P30DK58404) and the Vanderbilt-Ingram Cancer Center support grant (NCI P30CA68485). K.S. was supported by 5 T32 CA009582-26 and a postdoctoral fellowship (PF-13-303-01-DMC) from the American Cancer Society. Publisher Copyright: {\textcopyright} The Author(s) 2019.",
year = "2019",
month = may,
day = "7",
doi = "10.1093/nar/gkz127",
language = "English (US)",
volume = "47",
pages = "3921--3936",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "8",
}