Tyr1 phosphorylation promotes phosphorylation of Ser2 on the C-terminal domain of eukaryotic RNA polymerase II by P-TEFb

ELife
Joshua E MayfieldYan Zhang

Abstract

The Positive Transcription Elongation Factor b (P-TEFb) phosphorylates Ser2 residues of the C-terminal domain (CTD) of the largest subunit (RPB1) of RNA polymerase II and is essential for the transition from transcription initiation to elongation in vivo. Surprisingly, P-TEFb exhibits Ser5 phosphorylation activity in vitro. The mechanism garnering Ser2 specificity to P-TEFb remains elusive and hinders understanding of the transition from transcription initiation to elongation. Through in vitro reconstruction of CTD phosphorylation, mass spectrometry analysis, and chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we uncover a mechanism by which Tyr1 phosphorylation directs the kinase activity of P-TEFb and alters its specificity from Ser5 to Ser2. The loss of Tyr1 phosphorylation causes an accumulation of RNA polymerase II in the promoter region as detected by ChIP-seq. We demonstrate the ability of Tyr1 phosphorylation to generate a heterogeneous CTD modification landscape that expands the CTD's coding potential. These findings provide direct experimental evidence for a combinatorial CTD phosphorylation code wherein previously installed modifications direct the identity and abundance of subsequent coding events by i...Continue Reading

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Citations

May 14, 2020·Transcription·Danielle E LyonsMelanie Ott
Mar 8, 2021·Journal of Molecular Biology·Mukesh Kumar Venkat RamaniYan Zhang
Jun 20, 2021·Cellular and Molecular Life Sciences : CMLS·Sylvain Egloff
Jun 23, 2020·ACS Chemical Biology·Mukesh Kumar Venkat RamaniYan Jessie Zhang

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Datasets Mentioned

BETA
GSE131838

Methods Mentioned

BETA
immunoprecipitation
ChIP-seq
electrophoretic mobility shift assay
Dot blot
gel filtration
Protein Assay
dot blots

Software Mentioned

ImageJ
R Development Core Team
XCalibur Qual Browser
Studio
R
Integrative Genomics Viewer ( IGV )
R package smoother
SPSYsPT
Xtract
bowtie

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