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The small-molecule BMH-21 directly inhibits transcription elongation and DNA occupancy of RNA polymerase I in vivo and in vitro

Jacobs, Ruth Q. ; Huffines, Abigail K. ; Laiho, Marikki ; Schneider, David A.

The Journal of biological chemistry, 2022-01, Vol.298 (1), p.101450-101450, Article 101450 [Periódico revisado por pares]

United States: Elsevier Inc

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  • Título:
    The small-molecule BMH-21 directly inhibits transcription elongation and DNA occupancy of RNA polymerase I in vivo and in vitro
  • Autor: Jacobs, Ruth Q. ; Huffines, Abigail K. ; Laiho, Marikki ; Schneider, David A.
  • Assuntos: cancer therapeutics ; DNA, Ribosomal - genetics ; Heterocyclic Compounds, 4 or More Rings - pharmacology ; NET-seq ; RNA polymerase I ; RNA Polymerase I - genetics ; RNA Polymerase I - metabolism ; RNA Polymerase II - genetics ; rRNA ; transcription ; Transcription, Genetic - drug effects
  • É parte de: The Journal of biological chemistry, 2022-01, Vol.298 (1), p.101450-101450, Article 101450
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    These authors contributed equally to this work.
  • Descrição: Cancer cells are dependent upon an abundance of ribosomes to maintain rapid cell growth and proliferation. The rate-limiting step of ribosome biogenesis is ribosomal RNA (rRNA) synthesis by RNA polymerase I (Pol I). Therefore, a goal of the cancer therapeutic field is to develop and characterize Pol I inhibitors. Here, we elucidate the mechanism of Pol I inhibition by a first-in-class small-molecule BMH-21. To characterize the effects of BMH-21 on Pol I transcription, we leveraged high-resolution in vitro transcription assays and in vivo native elongating transcript sequencing (NET-seq). We find that Pol I transcription initiation, promoter escape, and elongation are all inhibited by BMH-21 in vitro. In particular, the transcription elongation phase is highly sensitive to BMH-21 treatment, as it causes a decrease in transcription elongation rate and an increase in paused Pols on the ribosomal DNA (rDNA) template. In vivo NET-seq experiments complement these findings by revealing a reduction in Pol I occupancy on the template and an increase in sequence-specific pausing upstream of G-rich rDNA sequences after BMH-21 treatment. Collectively, these data reveal the mechanism of action of BMH-21, which is a critical step forward in the development of this compound and its derivatives for clinical use.
  • Editor: United States: Elsevier Inc
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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