RNA Polymerase I Is Uniquely Vulnerable to the Small-Molecule Inhibitor BMH-21

Cancer cells require robust ribosome biogenesis to maintain rapid cell growth during tumorigenesis. Because RNA polymerase I (Pol I) transcription of the ribosomal DNA (rDNA) is the first and rate-limiting step of ribosome biogenesis, it has emerged as a promising anti-cancer target. Over the last d...

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Bibliographic Details
Published in:Cancers 2022-11, Vol.14 (22), p.5544
Main Authors: Jacobs, Ruth Q, Fuller, Kaila B, Cooper, Stephanie L, Carter, Zachariah I, Laiho, Marikki, Lucius, Aaron L, Schneider, David A
Format: Article
Language:English
Subjects:
Biosynthesis
Cancer
Cell growth
Chemical inhibitors
Clinical trials
DNA damage
DNA-directed RNA polymerase
Genomes
Health aspects
Ribosomal DNA
RNA polymerase
RNA polymerases
Therapeutic applications
Transcription
Tumorigenesis
Yeast
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Summary:Cancer cells require robust ribosome biogenesis to maintain rapid cell growth during tumorigenesis. Because RNA polymerase I (Pol I) transcription of the ribosomal DNA (rDNA) is the first and rate-limiting step of ribosome biogenesis, it has emerged as a promising anti-cancer target. Over the last decade, novel cancer therapeutics targeting Pol I have progressed to clinical trials. BMH-21 is a first-in-class small molecule that inhibits Pol I transcription and represses cancer cell growth. Several recent studies have uncovered key mechanisms by which BMH-21 inhibits ribosome biosynthesis but the selectivity of BMH-21 for Pol I has not been directly measured. Here, we quantify the effects of BMH-21 on Pol I, RNA polymerase II (Pol II), and RNA polymerase III (Pol III) in vitro using purified components. We found that BMH-21 directly impairs nucleotide addition by Pol I, with no or modest effect on Pols II and III, respectively. Additionally, we found that BMH-21 does not affect the stability of any of the Pols' elongation complexes. These data demonstrate that BMH-21 directly exploits unique vulnerabilities of Pol I.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14225544