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Discovery of highly reactive self-splicing group II introns within the mitochondrial genomes of human pathogenic fungi
- Source :
- Nucleic Acids Research
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
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.
- Subjects :
- AcademicSubjects/SCI00010
RNA Splicing
Histoplasma
Antifungal drug
Computational biology
DNA, Mitochondrial
Genome
Genetics
Humans
Base Sequence
Coccidioides
Virulence
biology
Nucleic Acid Enzymes
Intron
Computational Biology
RNA
Group II intron
biology.organism_classification
Introns
Mycoses
Genome, Mitochondrial
RNA splicing
Blastomyces
Nucleic Acid Conformation
Mitosporic Fungi
Mitoxantrone
Algorithms
Dimorphic fungus
Subjects
Details
- ISSN :
- 13624962 and 03051048
- Volume :
- 49
- Database :
- OpenAIRE
- Journal :
- Nucleic Acids Research
- Accession number :
- edsair.doi.dedup.....f774f19425f446f023e092727226d5ea