Quantitative global studies reveal differential translational control by start codon context across the fungal kingdom

Edward W J Wallace (1) , Corinne Maufrais (2, 3) , Jade Sales-Lee (4) , Laura R Tuck (1) , Luciana de Oliveira (3) , Frank Feuerbach (5) , Frederique Moyrand (3) , Prashanthi Natarajan (4) , Hiten D Madhani (4, 6) , Guilhem Janbon (3)

1 Ssynthsys - Centre for Synthetic and Systems Biology
2 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
3 Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens
4 Department of Biochemistry and Biophysics [San Francisco]
5 Génétique des Interactions macromoléculaires / Genetics of Macromolecular Interactions
6 Chan Zuckerberg BioHub [San Francisco, CA]

Eukaryotic protein synthesis generally initiates at a start codon defined by an AUG and its surrounding Kozak sequence context, but the quantitative importance of this context in different species is unclear. We tested this concept in two pathogenic Crypto-coccus yeast species by genome-wide mapping of translation and of mRNA 5 and 3 ends. We observed thousands of AUG-initiated upstream open reading frames (uORFs) that are a major contributor to translation repression. uORF use depends on the Kozak sequence context of its start codon, and uORFs with strong contexts promote nonsense-mediated mRNA decay. Transcript leaders in Cryptococcus and other fungi are substantially longer and more AUG-dense than in Saccharomyces. Numerous Crypto-coccus mRNAs encode predicted dual-localized proteins , including many aminoacyl-tRNA synthetases, in which a leaky AUG start codon is followed by a strong Kozak context in-frame AUG, separated by mitochondrial-targeting sequence. Analysis of other fungal species shows that such dual-localization is also predicted to be common in the ascomycete mould, Neurospora crassa. Kozak-controlled regulation is correlated with insertions in translational initiation factors in fidelity-determining regions that contact the initiator tRNA. Thus, start codon context is a signal that quantitatively programs both the expression and the structures of proteins in diverse fungi.

Domaines: Mycologie; Génétique

Edward W J Wallace, Corinne Maufrais, Jade Sales-Lee, Laura R Tuck, Luciana de Oliveira, et al.. Quantitative global studies reveal differential translational control by start codon context across the fungal kingdom. Nucleic Acids Research, 2020, 48 (5), pp.2312-2331. ⟨10.1093/nar/gkaa060⟩. ⟨pasteur-02651962⟩