The Levels of a Universally Conserved tRNA Modification Regulate Cell Growth

Rojas-Benítez, Diego; Thiaville, Patrick C.; Crécy‐Lagard, Valérie de; Glavic, Álvaro

doi:10.1074/jbc.m115.665406

Cited by 31 publications

(32 citation statements)

References 62 publications

(74 reference statements)

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“…Moreover, we demonstrate substantial cross-species rescue by fly Kae1 (and its partners) in yeast kae1 mutants, both in terms of growth capacity and in recovery of t6A-modified tRNAs. While this work was in preparation, similar observations using the kae1 transposon insertion alleles were reported by the Glavic group (Rojas-Benitez et al 2015). Our findings corroborate and extend their results.…”

Section: Confirmation Of the T6a Modification Pathway In A Metazoansupporting

confidence: 91%

“…The Glavic group reported foundational studies using transgenic RNAi against Drosophila Prpk/Bud32 (Ibar et al 2013), and their recent work (Rojas-Benitez et al 2015) and our current study extend this to genuine kae1 mutants. There are general similarities between the phenotypes of fruit fly and unicellular organism mutants, in that these genes are lethal (as in bacteria) and exhibit substantially defective growth (as in yeast).…”

Section: Differential Requirements Of T6a In Proliferating and Nonprosupporting

confidence: 62%

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An extensive allelic series of Drosophila kae1 mutants reveals diverse and tissue-specific requirements for t6A biogenesis

Lin

Smibert

Zhao

et al. 2015

RNA

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N 6 -threonylcarbamoyl-adenosine (t6A) is one of the few RNA modifications that is universally present in life. This modification occurs at high frequency at position 37 of most tRNAs that decode ANN codons, and stabilizes cognate anticodon-codon interactions. Nearly all genetic studies of the t6A pathway have focused on single-celled organisms. In this study, we report the isolation of an extensive allelic series in the Drosophila ortholog of the core t6A biosynthesis factor Kae1. kae1 hemizygous larvae exhibit decreases in t6A that correlate with allele strength; however, we still detect substantial t6A-modified tRNAs even during the extended larval phase of null alleles. Nevertheless, complementation of Drosophila Kae1 and other t6A factors in corresponding yeast null mutants demonstrates that these metazoan genes execute t6A synthesis. Turning to the biological consequences of t6A loss, we characterize prominent kae1 melanotic masses and show that they are associated with lymph gland overgrowth and ectopic generation of lamellocytes. On the other hand, kae1 mutants exhibit other phenotypes that reflect insufficient tissue growth. Interestingly, whole-tissue and clonal analyses show that strongly mitotic tissues such as imaginal discs are exquisitely sensitive to loss of kae1, whereas nonproliferating tissues are less affected. Indeed, despite overt requirements of t6A for growth of many tissues, certain strong kae1 alleles achieve and sustain enlarged body size during their extended larval phase. Our studies highlight tissue-specific requirements of the t6A pathway in a metazoan context and provide insights into the diverse biological roles of this fundamental RNA modification during animal development and disease.

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Section: Confirmation Of the T6a Modification Pathway In A Metazoansupporting

confidence: 91%

Section: Differential Requirements Of T6a In Proliferating and Nonprosupporting

confidence: 62%

An extensive allelic series of Drosophila kae1 mutants reveals diverse and tissue-specific requirements for t6A biogenesis

Lin

Smibert

Zhao

et al. 2015

RNA

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“…KEOPS/ EKC was early associated with different cellular processes: transcription regulation, telomere homeostasis, genome instability, chromosome segregation, and metabolic regulation (Srinivasan et al 2011). The t6A modification has been associated with cell growth regulation (Rojas-Benitez et al 2015) and the levels of t6A-modified tRNA strongly influence TORC1 activity (Rojas-Benitez et al 2015).…”

Section: The State Of the Trna Population In The Cellmentioning

confidence: 99%

Protein folding and tRNA biology

2017

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Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

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“…The last is present in tRNAs that pair A-starting codons (ANN) (Figure 1) [2]. This modification is universally conserved and has a paramount role for tRNA decoding function, as has been shown in yeast [8,9], archea [10], bacteria [11], and, recently by our laboratory [12] and others [13], in Drosophila . This modification was identified over 40 years ago [14,15,16]; however, the enzymes that synthetize it were only recently identified [8,9].…”

Section: Introductionmentioning

confidence: 97%

Modulation of the Proteostasis Machinery to Overcome Stress Caused by Diminished Levels of t6A‐Modified tRNAs in Drosophila

2017

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Transfer RNAs (tRNAs) harbor a subset of post-transcriptional modifications required for structural stability or decoding function. N6-threonylcarbamoyladenosine (t6A) is a universally conserved modification found at position 37 in tRNA that pair A-starting codons (ANN) and is required for proper translation initiation and to prevent frame shift during elongation. In its absence, the synthesis of aberrant proteins is likely, evidenced by the formation of protein aggregates. In this work, our aim was to study the relationship between t6A-modified tRNAs and protein synthesis homeostasis machinery using Drosophila melanogaster. We used the Gal4/UAS system to knockdown genes required for t6A synthesis in a tissue and time specific manner and in vivo reporters of unfolded protein response (UPR) activation. Our results suggest that t6A-modified tRNAs, synthetized by the threonyl-carbamoyl transferase complex (TCTC), are required for organismal growth and imaginal cell survival, and is most likely to support proper protein synthesis.

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The Levels of a Universally Conserved tRNA Modification Regulate Cell Growth

Cited by 31 publications

References 62 publications

An extensive allelic series of Drosophila kae1 mutants reveals diverse and tissue-specific requirements for t6A biogenesis

An extensive allelic series of Drosophila kae1 mutants reveals diverse and tissue-specific requirements for t6A biogenesis

Protein folding and tRNA biology

Modulation of the Proteostasis Machinery to Overcome Stress Caused by Diminished Levels of t6A‐Modified tRNAs in Drosophila

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