CDK9 inhibitors define elongation checkpoints at both ends of RNA polymerase II-transcribed genes

• Main Authors: Laitem, Clélia, Zaborowska, Justyna, Isa, Nur Firdaus, Kufs, Johann, Dienstbier, Martin, Murphy, Shona
• Format: Article
• Language: English; English
• Published: Nature Publishing Group 2015
• Subjects: Q Science (General); R Medicine (General)
• Online Access: http://irep.iium.edu.my/60432/1/2015-NSMB.pdf; http://irep.iium.edu.my/60432/7/60432_CDK9%20inhibitors%20define%20elongation_scopus.pdf; http://irep.iium.edu.my/60432/; https://www.nature.com/articles/nsmb.3000

Transcription through early-elongation checkpoints requires phosphorylation of negative transcription elongation factors (NTEFs) by the cyclin-dependent kinase (CDK)9. Using CDK9 inhibitors and global run-on sequencing (GRO-seq), we have mapped CDK9 inhibitor-sensitive checkpoints genome-wide in human (Homo sapiens) cells. Our data indicate that early-elongation checkpoints are a general feature of RNA polymerase (pol) II-transcribed human genes and occur independently of polymerase stalling. Pol II that has negotiated the early-elongation checkpoint can elongate in the presence of inhibitors but, remarkably, terminates transcription prematurely close to the terminal polyadenylation (poly(A)) site. Our analysis has revealed a hithertounsuspected poly(A)-associated elongation checkpoint, which has major implications for the regulation of gene expression. Interestingly, the pattern of modification of the carboxyl-terminal domain (CTD) of pol II terminated at this novel checkpoint largely mirrors the pattern normally found downstream of the poly(A) site, suggesting common mechanisms of termination