Journal
NUCLEIC ACIDS RESEARCH
Volume 39, Issue 14, Pages 6148-6160Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkr178
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Funding
- Centre National pour la Recherche Scientifique (CNRS)
- Agence Nationale pour la Recherche (ANR) [ANR-09-BLAN-0349-03, ANR-08-JCJC-0019-01]
- Netherlands Organization of Scientific Research (NWO) [021.002.035, 817.02.015, 050.71.057, 911.06.009, 016.108.607]
- Netherlands Bioinformatics Centre (NBIC)
- U.S. Department of Energy [DEFG0207ER64498]
- National Institutes of Health [R01 GM70641-01]
- CNRS
- Agence Nationale de la Recherche (ANR) [ANR-08-JCJC-0019, ANR-09-BLAN-0349] Funding Source: Agence Nationale de la Recherche (ANR)
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The EKC/KEOPS complex is universally conserved in Archaea and Eukarya and has been implicated in several cellular processes, including transcription, telomere homeostasis and genomic instability. However, the molecular function of the complex has remained elusive so far. We analyzed the transcriptome of EKC/KEOPS mutants and observed a specific profile that is highly enriched in targets of the Gcn4p transcriptional activator. GCN4 expression was found to be activated at the translational level in mutants via the defective recognition of the inhibitory upstream ORFs (uORFs) present in its leader. We show that EKC/KEOPS mutants are defective for the N6-threonylcarbamoyl adenosine modification at position 37 (t(6)A(37)) of tRNAs decoding ANN codons, which affects initiation at the inhibitory uORFs and provokes Gcn4 de-repression. Structural modeling reveals similarities between Kae1 and bacterial enzymes involved in carbamoylation reactions analogous to t(6)A(37) formation, supporting a direct role for the EKC in tRNA modification. These findings are further supported by strong genetic interactions of EKC mutants with a translation initiation factor and with threonine biosynthesis genes. Overall, our data provide a novel twist to understanding the primary function of the EKC/KEOPS and its impact on several essential cellular functions like transcription and telomere homeostasis.
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