@article{0aabd504ac8a4c3993f7412b346e8fc3,
title = "KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs",
abstract = "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.",
keywords = "CDK9, KAP1, RNA polymerase II, SMAD, TGF-β, TRIM28, cancer, chromatin reader, epigenetics, pausing",
author = "Bacon, {Curtis W.} and Ashwini Challa and Usman Hyder and Ashutosh Shukla and Borkar, {Aditi N.} and Juan Bayo and Jiuyang Liu and Wu, {Shwu Yuan} and Chiang, {Cheng Ming} and Kutateladze, {Tatiana G.} and Iv{\'a}n D'Orso",
note = "Funding Information: We thank members of the D'Orso laboratory for critical reading of the manuscript; L. Kraus, N. Conrad, and D. Corey for discussions; Y. Zhang for help with NMR data analysis; and the UTSW McDermott Center. The research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI114362, Welch Foundation grant I-1782, and CPRIT grant RP170572 (to I.D.). C.B. was supported by The Graduate Research Fellowship Program from the National Science Foundation (2016220513). U.H. was partially funded through the Green Fellows program and the SURF program at the University of Texas at Dallas and UTSW, respectively. A.N.B. was supported by the Sir Henry Wellcome postdoctoral fellowship from the Wellcome Trust, UK under award reference 103963/Z/14/Z and the Anne McLaren fellowship at the University of Nottingham. T.G.K. is supported by grants from the NIH. C.-M.C.?s research is supported by NIH grant 1RO1CA251698-01, CPRIT grants RP180349 and RP190077, and Welch Foundation grant I-1805. Conceptualization, I.D. and C.W.B.; Methodology, I.D. and C.W.B.; Investigation, C.W.B. A.C. U.H. A.S. J.L. and S.-Y.W.; Formal Analysis, C.W.B. A.N.B. J.B. and J.L.; Writing ? Original Draft, I.D. and C.W.B.; Writing ? Review & Editing. I.D. C.W.B. U.H. and J.B.; Supervision, I.D. T.G.K. and C.-M.C.; Funding Acquisition, I.D. The authors declare no competing interests. Funding Information: We thank members of the D{\textquoteright}Orso laboratory for critical reading of the manuscript; L. Kraus, N. Conrad, and D. Corey for discussions; Y. Zhang for help with NMR data analysis; and the UTSW McDermott Center. The research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI114362 , Welch Foundation grant I-1782 , and CPRIT grant RP170572 (to I.D.). C.B. was supported by The Graduate Research Fellowship Program from the National Science Foundation ( 2016220513 ). U.H. was partially funded through the Green Fellows program and the SURF program at the University of Texas at Dallas and UTSW , respectively. A.N.B. was supported by the Sir Henry Wellcome postdoctoral fellowship from the Wellcome Trust , UK under award reference 103963/Z/14/Z and the Anne McLaren fellowship at the University of Nottingham . T.G.K. is supported by grants from the NIH . C.-M.C.{\textquoteright}s research is supported by NIH grant 1RO1CA251698-01 , CPRIT grants RP180349 and RP190077 , and Welch Foundation grant I-1805 . Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jun,
day = "18",
doi = "10.1016/j.molcel.2020.04.024",
language = "English (US)",
volume = "78",
pages = "1133--1151.e14",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}