BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.
Mol Cell
; 67(1): 5-18.e19, 2017 Jul 06.
Article
in En
| MEDLINE
| ID: mdl-28673542
ABSTRACT
Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation. In contrast to the selective effect of bromodomain inhibition on transcription, BET degradation prompts a collapse of global elongation that phenocopies CDK9 inhibition. Notably, BRD4 loss does not directly affect CDK9 localization. These studies, performed in translational models of T cell leukemia, establish a mechanism-based rationale for the development of BET bromodomain degradation as cancer therapy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
/
Nuclear Proteins
/
Cyclin-Dependent Kinase 9
/
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/
Transcription Elongation, Genetic
Type of study:
Prognostic_studies
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2017
Type:
Article
Affiliation country:
Austria