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Tytuł pozycji:

KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs.

Tytuł:
KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs.
Autorzy:
Bacon CW; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Biological Chemistry Graduate Program, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Challa A; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Hyder U; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Shukla A; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Borkar AN; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Bayo J; Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Derqui-Pilar, Buenos Aires 1629, Argentina.
Liu J; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Wu SY; Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Chiang CM; Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kutateladze TG; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
D'Orso I; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: .
Źródło:
Molecular cell [Mol Cell] 2020 Jun 18; Vol. 78 (6), pp. 1133-1151.e14. Date of Electronic Publication: 2020 May 12.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
Język:
English
Imprint Name(s):
Publication: Cambridge Ma : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1997-
MeSH Terms:
RNA Polymerase II/*metabolism
Tripartite Motif-Containing Protein 28/*metabolism
Acetylation ; Cell Line, Tumor ; Chromatin/genetics ; Chromatin/metabolism ; Cyclin-Dependent Kinase 9/metabolism ; Gene Expression Regulation/genetics ; Histones/metabolism ; Humans ; Oncogenes/genetics ; Promoter Regions, Genetic/genetics ; Protein Processing, Post-Translational/genetics ; RNA Polymerase II/genetics ; Smad2 Protein/metabolism ; Transcription Factors/metabolism ; Transcription, Genetic ; Tripartite Motif-Containing Protein 28/genetics
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Grant Information:
R01 CA252707 United States CA NCI NIH HHS; R01 GM135671 United States GM NIGMS NIH HHS; R01 AI114362 United States AI NIAID NIH HHS; R01 CA251698 United States CA NCI NIH HHS; United Kingdom WT_ Wellcome Trust; R01 HL151334 United States HL NHLBI NIH HHS
Contributed Indexing:
Keywords: CDK9; KAP1; RNA polymerase II; SMAD; TGF-β; TRIM28; cancer; chromatin reader; epigenetics; pausing
Substance Nomenclature:
0 (Chromatin)
0 (Histones)
0 (SMAD2 protein, human)
0 (Smad2 Protein)
0 (Transcription Factors)
EC 2.3.2.27 (TRIM28 protein, human)
EC 2.3.2.27 (Tripartite Motif-Containing Protein 28)
EC 2.7.11.22 (CDK9 protein, human)
EC 2.7.11.22 (Cyclin-Dependent Kinase 9)
EC 2.7.7.- (RNA Polymerase II)
Entry Date(s):
Date Created: 20200514 Date Completed: 20200916 Latest Revision: 20240105
Update Code:
20240105
PubMed Central ID:
PMC7305985
DOI:
10.1016/j.molcel.2020.04.024
PMID:
32402252
Czasopismo naukowe
Precise control of the RNA polymerase II (RNA Pol II) cycle, including pausing and pause release, maintains transcriptional homeostasis and organismal functions. Despite previous work to understand individual transcription steps, we reveal a mechanism that integrates RNA Pol II cycle transitions. Surprisingly, KAP1/TRIM28 uses a previously uncharacterized chromatin reader cassette to bind hypo-acetylated histone 4 tails at promoters, guaranteeing continuous progression of RNA Pol II entry to and exit from the pause state. Upon chromatin docking, KAP1 first associates with RNA Pol II and then recruits a pathway-specific transcription factor (SMAD2) in response to cognate ligands, enabling gene-selective CDK9-dependent pause release. This coupling mechanism is exploited by tumor cells to aberrantly sustain transcriptional programs commonly dysregulated in cancer patients. The discovery of a factor integrating transcription steps expands the functional repertoire by which chromatin readers operate and provides mechanistic understanding of transcription regulation, offering alternative therapeutic opportunities to target transcriptional dysregulation.
Competing Interests: Declaration of Interests The authors declare no competing interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)

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