The CDK7 inhibitor THZ1 alters RNA polymerase dynamics at the 5' and 3' ends of genes

Nucleic Acids Research
Shilpa SampathiScott W Hiebert

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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Citations

May 10, 2019·Cancers·Feda H Hamdan, Steven A Johnsen
Dec 7, 2019·The Journal of Biological Chemistry·H Karimi KinyamuTrevor K Archer
Jun 20, 2020·EMBO Molecular Medicine·Athanasios R PaliourasMichela Garofalo
Jan 11, 2020·Frontiers in Oncology·Raoul Tibes, James M Bogenberger
Jan 1, 2021·Molecular Cell·Kristy R StengelScott W Hiebert
Nov 14, 2020·Expert Opinion on Investigational Drugs·Hanzhi LiangHao Fang
Jul 25, 2021·International Journal of Molecular Sciences·Alvina I KhamidullinaAlexandra V Bruter

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Datasets Mentioned

BETA
GM-CSF
GSE102243

Methods Mentioned

BETA
ChIP
flow cytometry
co-immunoprecipitation
Co-IP
ChIP-seq
ChIPseq
RNAseq
ChIP-exo
PRO-seq
immunoprecipitation

Software Mentioned

Bowtie2
IGV
FastX
GSEA
cutadapt
PROseq IGV browser
N R S A
DESeq2
PROseq

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