SPT5 roles in transcriptional elongation

Abstract Diffuse intrinsic pontine glioma (DIPG) is highly aggressive brain stem tumor and needed to develop novel therapeutic agents for the treatment. The super elongation complex (SEC) is essential for transcription elongation through release of RNA polymerase II (Pol II). We found that AFF4, a scaffold protein of the SEC, is required for the growth of H3K27M-mutant DIPG cells. In addition, the small molecule SEC inhibitor, KL-1, increased promoter-proximal pausing of Pol II, and reduced transcription elongation, resulting in down-regulate cell cycle, transcription and DNA repair genes. KL-1 treatment decreased cell growth and increased apoptosis in H3K27M-mutant DIPG cells, and prolonged animal survival in our human H3K27M-mutant DIPG xenograft model. Our results demonstrate that the SEC disruption by KL-1 is a novel therapeutic strategy for H3K27M-mutant DIPG.

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4sUDRB-seq: measuring genomewide transcriptional elongation rates and initiation frequencies within cells

Genome Biology ◽

10.1186/gb-2014-15-5-r69 ◽

2014 ◽

Vol 15 (5) ◽

Cited By ~ 80

Author(s):

Gilad Fuchs ◽

Yoav Voichek ◽

Sima Benjamin ◽

Shlomit Gilad ◽

Ido Amit ◽

...

Keyword(s):

Transcriptional Elongation

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Ash1l Methylates Lys36 of Histone H3 Independently of Transcriptional Elongation to Counteract Polycomb Silencing

PLoS Genetics ◽

10.1371/journal.pgen.1003897 ◽

2013 ◽

Vol 9 (11) ◽

pp. e1003897 ◽

Cited By ~ 38

Author(s):

Hitomi Miyazaki ◽

Ken Higashimoto ◽

Yukari Yada ◽

Takaho A. Endo ◽

Jafar Sharif ◽

...

Keyword(s):

Histone H3 ◽

Transcriptional Elongation

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Regulation of P-TEFb Elongation Complex Activity by CDK9 Acetylation

Molecular and Cellular Biology ◽

10.1128/mcb.00857-06 ◽

2007 ◽

Vol 27 (13) ◽

pp. 4641-4651 ◽

Cited By ~ 40

Author(s):

Junjiang Fu ◽

Ho-Geun Yoon ◽

Jun Qin ◽

Jiemin Wong

Keyword(s):

Rna Polymerase Ii ◽

Elongation Factor ◽

Transcriptional Elongation ◽

Elongation Complex ◽

Complex Activity ◽

Interacting Protein ◽

Pol Ii ◽

Carboxy Terminal

ABSTRACT P-TEFb, comprised of CDK9 and a cyclin T subunit, is a global transcriptional elongation factor important for most RNA polymerase II (pol II) transcription. P-TEFb facilitates transcription elongation in part by phosphorylating Ser2 of the heptapeptide repeat of the carboxy-terminal domain (CTD) of the largest subunit of pol II. Previous studies have shown that P-TEFb is subjected to negative regulation by forming an inactive complex with 7SK small RNA and HEXIM1. In an effort to investigate the molecular mechanism by which corepressor N-CoR mediates transcription repression, we identified HEXIM1 as an N-CoR-interacting protein. This finding led us to test whether the P-TEFb complex is regulated by acetylation. We demonstrate that CDK9 is an acetylated protein in cells and can be acetylated by p300 in vitro. Through both in vitro and in vivo assays, we identified lysine 44 of CDK9 as a major acetylation site. We present evidence that CDK9 is regulated by N-CoR and its associated HDAC3 and that acetylation of CDK9 affects its ability to phosphorylate the CTD of pol II. These results suggest that acetylation of CDK9 is an important posttranslational modification that is involved in regulating P-TEFb transcriptional elongation function.

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