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

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

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1133-1151.e14
JournalMolecular cell
Volume78
Issue number6
DOIs
StatePublished - Jun 18 2020

Keywords

  • CDK9
  • KAP1
  • RNA polymerase II
  • SMAD
  • TGF-β
  • TRIM28
  • cancer
  • chromatin reader
  • epigenetics
  • pausing

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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