TY - JOUR
T1 - 9-Aminoacridine Inhibits Ribosome Biogenesis by Targeting Both Transcription and Processing of Ribosomal RNA
AU - Anikin, Leonid
AU - Pestov, Dimitri G.
N1 - Funding Information:
Funding: This research was supported by grants R01GM074091 and R03CA246009 from the National Institutes of Health, USA.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - Aminoacridines, used for decades as antiseptic and antiparasitic agents, are prospective candidates for therapeutic repurposing and new drug development. Although the mechanisms behind their biological effects are not fully elucidated, they are most often attributed to the acridines’ ability to intercalate into DNA. Here, we characterized the effects of 9-aminoacridine (9AA) on pre-rRNA metabolism in cultured mammalian cells. Our results demonstrate that 9AA inhibits both transcription of the ribosomal RNA precursors (pre-rRNA) and processing of the already synthesized pre-rRNAs, thereby rapidly abolishing ribosome biogenesis. Using a fluorescent intercalator displacement assay, we further show that 9AA can bind to RNA in vitro, which likely contributes to its ability to inhibit post-transcriptional steps in pre-rRNA maturation. These findings extend the arsenal of small-molecule compounds that can be used to block ribosome biogenesis in mammalian cells and have implications for the pharmacological development of new ribosome biogenesis inhibitors.
AB - Aminoacridines, used for decades as antiseptic and antiparasitic agents, are prospective candidates for therapeutic repurposing and new drug development. Although the mechanisms behind their biological effects are not fully elucidated, they are most often attributed to the acridines’ ability to intercalate into DNA. Here, we characterized the effects of 9-aminoacridine (9AA) on pre-rRNA metabolism in cultured mammalian cells. Our results demonstrate that 9AA inhibits both transcription of the ribosomal RNA precursors (pre-rRNA) and processing of the already synthesized pre-rRNAs, thereby rapidly abolishing ribosome biogenesis. Using a fluorescent intercalator displacement assay, we further show that 9AA can bind to RNA in vitro, which likely contributes to its ability to inhibit post-transcriptional steps in pre-rRNA maturation. These findings extend the arsenal of small-molecule compounds that can be used to block ribosome biogenesis in mammalian cells and have implications for the pharmacological development of new ribosome biogenesis inhibitors.
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U2 - 10.3390/ijms23031260
DO - 10.3390/ijms23031260
M3 - Article
C2 - 35163183
AN - SCOPUS:85123120146
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 3
M1 - 1260
ER -