1. Discovery of highly reactive self-splicing group II introns within the mitochondrial genomes of human pathogenic fungi.
- Author
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Liu T and Pyle AM
- Subjects
- Algorithms, Base Sequence, Blastomyces genetics, Blastomyces physiology, Coccidioides genetics, Coccidioides physiology, Computational Biology methods, DNA, Mitochondrial chemistry, Histoplasma genetics, Histoplasma physiology, Humans, Mitosporic Fungi classification, Mitosporic Fungi pathogenicity, Mitoxantrone pharmacology, Mycoses microbiology, Nucleic Acid Conformation, RNA Splicing drug effects, Virulence genetics, DNA, Mitochondrial genetics, Genome, Mitochondrial genetics, Introns genetics, Mitosporic Fungi genetics, RNA Splicing genetics
- Abstract
Fungal pathogens represent an expanding global health threat for which treatment options are limited. Self-splicing group II introns have emerged as promising drug targets, but their development has been limited by a lack of information on their distribution and architecture in pathogenic fungi. To meet this challenge, we developed a bioinformatic workflow for scanning sequence data to identify unique RNA structural signatures within group II introns. Using this approach, we discovered a set of ubiquitous introns within thermally dimorphic fungi (genera of Blastomyces, Coccidioides and Histoplasma). These introns are the most biochemically reactive group II introns ever reported, and they self-splice rapidly under near-physiological conditions without protein cofactors. Moreover, we demonstrated the small molecule targetability of these introns by showing that they can be inhibited by the FDA-approved drug mitoxantrone in vitro. Taken together, our results highlight the utility of structure-based informatic searches for identifying riboregulatory elements in pathogens, revealing a striking diversity of reactive self-splicing introns with great promise as antifungal drug targets., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2021
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