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

Bacon, Curtis W.; Challa, Ashwini; Hyder, Usman; Shukla, Ashutosh; Borkar, Aditi N.; Bayo, Juan; Liu, Jiuyang; Wu, Shwu-Yuan; Kutateladze, Tatiana G.; Chiang, Cheng-Ming; D�Orso, Iv�n

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.

Citation

Bacon, C. W., Challa, A., Hyder, U., Shukla, A., Borkar, A. N., Bayo, J., …D’Orso, I. (2020). KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs. Molecular Cell, 78(6), 1133-1151.e14. https://doi.org/10.1016/j.molcel.2020.04.024

• Journal Article Type: Article
• Acceptance Date: Apr 17, 2020
• Online Publication Date: May 12, 2020
• Publication Date: Jun 18, 2020
• Deposit Date: Sep 14, 2020
• Publicly Available Date: May 13, 2021
• Journal: Molecular Cell
• Print ISSN: 1097-2765
• Electronic ISSN: 1097-4164
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 78
• Issue: 6
• Pages: 1133-1151.e14
• DOI: https://doi.org/10.1016/j.molcel.2020.04.024
• Keywords: Cell Biology; Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/4903623
• Publisher URL: https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30266-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276520302665%3Fshowall%3Dtrue#articleInformation
• Additional Information: This article is maintained by: Elsevier; Article Title: KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs; Journal Title: Molecular Cell; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.molcel.2020.04.024; Content Type: article; Copyright: © 2020 Elsevier Inc.