Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

Nadine Czudnochowski, Christian A. Bösken and Matthias Geyer ()
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Nadine Czudnochowski: Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie
Christian A. Bösken: Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie
Matthias Geyer: Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract Phosphorylation of RNA polymerase II carboxy-terminal domain (CTD) in hepta-repeats YSPTSPS regulates eukaryotic transcription. Whereas Ser5 is phosphorylated in the initiation phase, Ser2 phosphorylation marks the elongation state. Here we show that the positive transcription elongation factor P-TEFb is a Ser5 CTD kinase that is unable to create Ser2/Ser5 double phosphorylations, while it exhibits fourfold higher activity on a CTD substrate pre-phosphorylated at Ser7 compared with the consensus hepta-repeat or the YSPTSPK variant. Mass spectrometry reveals an equal number of phosphorylations to the number of hepta-repeats provided, yet the mechanism of phosphorylation is distributive despite the repetitive nature of the substrate. Inhibition of P-TEFb activity is mediated by two regions in Hexim1 that act synergistically on Cdk9 and Cyclin T1. HIV-1 Tat/TAR abrogates Hexim1 inhibition to stimulate transcription of viral genes but does not change the substrate specificity. Together, these results provide insight into the multifaceted pattern of CTD phosphorylation.

Date: 2012
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DOI: 10.1038/ncomms1846

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