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Review

The translation factors of Drosophila melanogaster

Steven J. MarygoldFlyBase, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UKCorrespondence[email protected] [email protected]
,
Helen AttrillFlyBase, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
&
Paul LaskoDepartment of Biology, McGill University, Bellini Life Sciences Complex, Montreal, Quebec, CanadaCorrespondence[email protected] [email protected]
Pages 65-74 | Received 15 Jun 2016, Accepted 18 Jul 2016, Published online: 05 Sep 2016

ABSTRACT

Synthesis of polypeptides from mRNA (translation) is a fundamental cellular process that is coordinated and catalyzed by a set of canonical ‘translation factors’. Surprisingly, the translation factors of Drosophila melanogaster have not yet been systematically identified, leading to inconsistencies in their nomenclature and shortcomings in functional (Gene Ontology, GO) annotations. Here, we describe the complete set of translation factors in D. melanogaster, applying nomenclature already in widespread use in other species, and revising their functional annotation. The collection comprises 43 initiation factors, 12 elongation factors, 3 release factors and 6 recycling factors, totaling 64 of which 55 are cytoplasmic and 9 are mitochondrial. We also provide an overview of notable findings and particular insights derived from Drosophila about these factors. This catalog, together with the incorporation of the improved nomenclature and GO annotation into FlyBase, will greatly facilitate access to information about the functional roles of these important proteins.

Introduction

The process of protein synthesis can be divided into 4 phases: initiation, elongation, termination (or release) and recycling. Each phase involves the ribosome, transfer RNA (tRNAs) and a series of sequentially acting ‘translation factors’ operating upon messenger RNA (mRNA) substrates. Together, these components comprise the core translational machinery that converts the genetic code into polypeptide chains in all cells.

The translational machinery operating in the cytoplasm and mitochondria of eukaryotic cells is distinct. Cytoplasmic (or ‘eukaryotic’) translation factors are encoded by the nuclear genome and direct the bulk of cellular protein synthesis. The initiation phase of cytoplasmic translation is the most highly regulated, which is reflected by the large number of cytoplasmic initiation factors – in mammals, at least 12 distinct initiation factors (involving ∼35 separate proteins) have been characterized, compared to just 2–3 elongation factors, 2 release factors and 1 major recycling factor.Citation1,2 Mitochondrial translation utilizes a similar, albeit much smaller, set of mitochondria-specific factors, which are more closely related to prokaryotic translation factors. These are also encoded by nuclear genes but are targeted to the mitochondria where they catalyze production of the 13 proteins encoded by the mitochondrial genome. Only 8 mitochondrial translation factors exist in mammals and, in contrast to the situation in the cytoplasm, there is no expansion in the set of initiation factors.Citation3

Interest in cytoplasmic and mitochondrial translation factors has grown beyond basic research in recent years because their deregulation is linked to an increasing number of human cancers and other diseases.Citation4-6 The fruit fly, Drosophila melanogaster, has proved to be an effective model in which to study both the canonical functions and pathological roles of the protein synthesis machinery,Citation7 and many individual fly translation factors have been characterized. However, the full set of translation factors in this model organism has not yet been systematically identified or annotated, thereby hindering access to existing data as well as the development of further research.

We are aware of 2 previous studies that have attempted to catalog the translation factors of D. melanogaster (Supplementary Table 1). The first was performed immediately after the publication of the initial genome sequence - it identified 47 cytoplasmic translation factors based on similarity to their mammalian counterparts.Citation8 However, this early list omitted several proteins that have only since been recognized as translation factors, while mitochondrial translation factors were not examined. A later study identified 68 potential translation factors based on Gene Ontology (GO) annotations and sequence similarity searches (see additional data file 6 in ref.Citation9). Although this longer list included more bona fide cytoplasmic factors, it is now apparent that it also contained many false positive hits; again, mitochondrial factors were not identified. The absence of an accurate reference set of fly translation factors has resulted in a haphazard nomenclature for these genes/proteins in FlyBase, the online database of Drosophila research.Citation10

In order to directly address these issues, we have conducted a new analysis of the complement of genes encoding the canonical translation factors in D. melanogaster, taking into account recent molecular, genetic and biochemical studies conducted in flies and in other eukaryotes. We find that there are 55 genes encoding cytoplasmic translation factors and 9 genes coding for mitochondrial translation factors, making 64 factors in total. Moreover, we have updated all relevant GO annotations in FlyBase and propose a systematic nomenclature based on common usage in flies and the wider community. We also provide an overview of the current state of characterization of the different translation factors in flies, highlighting particularly significant or noteworthy aspects.

Identification of translation factors

We employed a 3-pronged approach to identify the full set of genes encoding the canonical cytoplasmic and mitochondrial translation factors in D. melanogaster. (We define ‘canonical translation factors’ as those classified as such in several recent reviews in the field.Citation1-3,6,11,12). First, the sets of genes identified by previous studies were compiled and integrated.Citation8,9 Second, a de novo search was conducted by searching FlyBase Citation10 (release FB2016_03) for D. melanogaster genes annotated with relevant GO terms. Third, the established sets of mammalian cytoplasmic and mitochondrial translation factors Citation1-3,6,11,12 were compiled and their D. melanogaster orthologs were determined using the DIOPT integrative ortholog prediction tool.Citation13 These analyses identified a total of 64 canonical translation factors - 13 of which are identified/named for the first time here (including two-thirds of the mitochondrial complement), while a further 16 are renamed to use conventional nomenclature. Furthermore, the functional annotations for all identified genes have been updated to reflect current knowledge, resulting in the addition of >30 GO annotations and the removal of >60 GO annotations. These data are given in full in Supplementary Table 1 and are summarized in .

Cytoplasmic translation factors

Initiation factors

Translation initiation involves the assembly of elongation-competent 80S ribosomes in which the anticodon of the initiator methionyl-tRNA is base-paired with the AUG start codon of the mRNA. (See refs. Citation1,6,14 for recent reviews and details of individual protein functions.) In brief, initiation begins with the formation of a ternary complex of initiator methionyl-tRNA and GTP-bound eukaryotic initiation factor (eIF)2, which then assembles into a preinitiation complex (PIC) with the small (40S) ribosomal subunit and eIF1, eIF1A, eIF3 and eIF5. Next, the PIC attaches to the capped region of the mRNA in a step that involves the poly(A)-binding protein (PABP), the helicase eIF4A (whose activity is enhanced by eIF4B and eIF4H), the cap-binding protein eIF4E, and the scaffold protein eIF4G. The PIC then scans along the 5′ untranslated region (UTR) to the initiation codon, at which point eIF5 promotes the conversion of eIF2 to its GDP-bound state, resulting in the displacement of most eIFs. The GTPase eIF5B then mediates the joining of the large (60S) ribosomal subunit to form the 80S ribosome, after which eIF5B is released together with eIF1A. The guanine exchange factor eIF2B is required to reload eIF2 with GTP, and may also dissociate an eIF5–eIF2 complex, in order that these factors may participate in subsequent rounds of initiation.

We identified a total of 41 genes encoding cytoplasmic eIF proteins in flies (). As in mammals, most eIF genes are present as single copies, including those encoding eIF1, eIF1A,Citation15 the 3 subunits of eIF2,Citation16-18 the 5 subunits of eIF2B,Citation19 most eIF3 subunits, eIF4B,Citation20 eIF5 and eIF5B.Citation21 Flies also harbor a single gene encoding functional eIF4A,Citation22,23 whereas mammals possess 2 paralogs.Citation1,6 Of these single copy genes, eIF2α and eIF2γ are notable for being characterized as haplo-insufficient – eIF2α is a likely Minute locus, while eIF2γ appears to be haplo-lethal.Citation9

Table 1. D. melanogaster cytoplasmic translation factors.

Other eIFs are encoded by multiple genes in flies (). Most strikingly, there are 7 genes encoding eIF4E isoforms, as opposed to just 3 in mammals.Citation24,25 Fly eIF4E1 is the canonical form and is expressed ubiquitously.Citation24,26,27 eIF4EHP and eIF4E6 are exceptional in that they harbor amino acid substitutions that prevent binding to eIF4G Citation24; indeed, eIF4EHP acts as a translational inhibitor of caudal, hunchback and belle mRNAs, and thus plays a key role in patterning the oocyte and the early embryo.Citation28-30 eIF4E3 is a testis-specific protein that is required for spermatogenesis and male fertility.Citation31,32 Although little functional information is available for eIF4E4, eIF4E5, eIF4E6 and eIF4E7, it is notable that their expression is also enriched in the male germline Citation33,34 (Supplementary Table 2), suggesting specialized roles in this tissue. Flies also have duplicate genes encoding eIF4G, eIF4H, and the eIF3 subunits eIF3d, eIF3f and eIF3g. Again, it is significant that the expression of one member of each of these pairs (eIF4G2, eIF4H2 eIF3d2, eIF3f2, and eIF3g2) is specifically enriched in the testis Citation33-36 (Supplementary Table 2). Of these 5 pairs, only eIF4G has so far been characterized functionally: eIF4G1 is the major, canonical form,Citation37 whereas eIF4G2 has divergent N- and C-termini and is essential for the proper meiotic divisions during spermatogenesis.Citation31,35,36

An additional 6 proteins are classified as ‘non-canonical’ initiation factors (Supplementary Table 1).Citation1 Fly eIF2A (CG7414) is the ortholog of human EIF2A, which is an alternative initiator tRNA-binding protein, and fly NAT1 (CG3845) Citation38-40 is the ortholog of human eIF4G2 (also known as NAT1/p97/DAP5), which has sequence similarity to the C-terminus of EIF4G1. Both human proteins are implicated in mediating cap-independent (i.e. internal ribosome entry site, IRES) translation under conditions of cellular stress,Citation41,42 while fly NAT1 regulates translation of specific mRNAs important for germband extension, metamorphosis and circadian rhythm.Citation39,40 CG1582 appears to be the fly ortholog of the human DHX29 helicase, which promotes ribosomal scanning through highly structured 5′ UTRs.Citation43,44 Mxt (CG2950) appears to be an eIF4G analog that binds eIF3 and eIF4E and may serve as an alternative to the canonical eIF4G to promote translation in certain tissues.Citation45 It has no clear mammalian ortholog. PolyA-binding protein, encoded by the pAbp (CG5119) gene in flies,Citation46 is a multifunctional RNA-binding protein with an essential role in enhancing translation initiation.Citation47 Finally, fly eIF6 (CG17611) Citation48 is the ortholog of human EIF6, which has an indirect role in translation by preventing ribosomal subunit joining until large subunit biogenesis is complete.Citation49 In flies, eIF6 down-regulates Wnt signaling through selective inhibition of β-catenin translation.Citation48

It is worth noting that a few other fly genes and proteins have acquired symbols or synonyms that suggest a role in translational initiation that they do not in fact possess. Two proteins, originally named eIF5A and eIF2D, have since been implicated in translation elongation or recycling, respectively, rather than in the initiation phase - these cases are discussed in the relevant sections below. Fly eIF4AIII (CG7483) is the ortholog of mammalian EIF4A3 (88% identity) – this protein has sequence similarity to eIF4A but has no known initiation factor activity.Citation25 Rather, it has been demonstrated to be a core component of the exon junction complex that functions in nonsense-mediated mRNA decay.Citation50 CG4849 has been referred to as EFTUD2 or eEF2, implying a role in translation elongation, but despite sequence similarity to eEF2, it actually functions in pre-mRNA splicing.Citation51 Finally, eIF2C1 and eIF2C2 are obsolete designations for the Argonaute family proteins Citation52 (AGO1 and AGO2 in flies), while eIF5C is an obsolete term for the translational inhibitor now known as Krasavietz.Citation53

Elongation factors

Translation elongation is the step-wise increase in the length of the growing peptide chain by the addition of single amino acids through the action of the ribosome, aminoacyl-tRNAs and 2 major eukaryotic elongation factors, eEF1 and eEF2. (See refs. Citation2,11 for recent reviews and details of individual protein functions.) Briefly, the eEF1 complex, comprising 4 subunits, catalyzes the delivery of aminoacyl-tRNA to the ribosome in a GTP-dependent manner – eEF1α is the main player in this process, while eEF1β and eEF1δ are guanine exchange factors for eEF1α, while eEF1γ is thought to have a structural role. eEF2 acts as the translocase to move the ribosome down the mRNA one codon at a time. Recently, the role of the protein originally designated eIF5A has been clarified, and it has been shown to function in the elongation phase. We therefore refer to it as eEF5 herein, as proposed in ref. Citation54 eEFSec is a specialized elongation factor that is required for decoding of the UGA stop codon as selenocysteine in mRNAs containing a specific SECIS element, resulting in the production of selenoproteins.Citation55

Flies contain the same complement of genes encoding eEFs as mammals: 2 copies of eEF1α,Citation56 and one copy each of eEF1β,  eEF1γCitation57, eEF1δ, eEF2,Citation58 eEF5 Citation59 and eEFSec Citation60 (). Of the 2 eEF1α isoforms, eEF1α1 is expressed at high levels in all tissues throughout development and appears to be the major form, while eEF1α2 expression is more restricted with peaks in the nervous system during pupal stages.Citation33,61 As in other eukaryotes, eEF5 is the only protein in flies known to harbor a hypusine residue, which is a post-translational modification of a lysine.Citation54,59 Importantly, the function of hypusine-modified eEF5 in translation elongation has been confirmed in flies.Citation59

Release/termination factors

Translation termination occurs at the end of the coding sequence of the mRNA, when the ribosome encounters a stop codon - UAA, UAG or UGA (in the absence of a SECIS element). (See refs.Citation2,12 for further details.) Just 2 release factors are involved, eRF1 and eRF3. (Note that there is not a eukaryotic release factor named ‘eRF2’.) eRF1 recognizes the stop codon and catalyzes the hydrolysis of the peptidyl-tRNA to release the completed polypeptide chain, while eRF3 enhances this process in a GTP-dependent manner.

As in mammals, the 2 fly eRFs are encoded by single-copy genes (). Interestingly, mutations in each of the fly genes were isolated in a genetic screen as ‘nonsense suppressors’ because disruption of eRF function results in increased read-through of a subset of nonsense mutations in other genes, leading to phenotypic suppression.Citation62

Recycling and reinitiation factors

The process of recycling involves the disassembly and release of the 80S ribosome, deacylated tRNA and eRF1 from the mRNA. (See refs. Citation2,12,63 for further details.) The first step is the dissociation of the 60S ribosomal subunit, which is mediated by the ABCE1 ATPase. This is followed by the ejection of the deacylated tRNA and dissociation of the 40S subunit – this step appears to be stimulated either by a subset of canonical initiation factors, including eIF1, eIF1A and eIF3j, or through a second mechanism involving eIF2D (also known as ligatin) or the MCTS1–DENR complex. The separated ribosomal subunits then associate with initiation factors again to allow further rounds of initiation. The related process of translation reinitiation, where the termination reaction is followed by initiation on the same mRNA molecule, is mechanistically similar to recycling and at least some of the same factors are implicated.

Flies contain single copy genes encoding all these factors (). Notably, the first indications that ABCE1 (encoded by the pixie gene) had a role in translational regulation came through genetic studies in flies,Citation64 and follow-up studies were among the first to demonstrate the association of ABCE1 with eIFs and the 40S ribosome.Citation65 Furthermore, research in flies has demonstrated a specific function of the MCTS1–DENR complex in translation reinitiation - mRNAs containing upstream open reading frames selectively require MCTS1–DENR for their proper translation in proliferating cells.Citation66

Mitochondrial translation factors

The mitochondrial translation system of eukaryotic cells is much simpler than its cytoplasmic counterpart, comprising a total of just 9 canonical translation factors that are homologous to bacterial factors. (See refs. Citation3,5,67 for recent reviews and detailed information on the function of individual proteins.) All key components of the translation system in this organelle (i.e., ribosomal proteins, tRNAs, aminoacyl tRNA synthetases, in addition to translation factors) exist as mitochondrial-specific forms, distinct from their cytoplasmic equivalents.

The mitochondrial translation process may be summarized as follows. Initiation begins with the association of mitochondrial initiation factor 3 (mIF3) to the 28S small ribosomal subunit, followed by GTP-bound mIF2 and the initiator tRNA. (Note that there is not a mitochondrial initiation factor named ‘mIF1’.) The substrate mRNA then binds, followed by association of the large 39S ribosomal subunit, GTP hydrolysis and exiting of the mIFs. The elongation phase proceeds through cycles of mEFTu-GTP bringing the aminoacyl-tRNA to the ribosome coupled with GTP hydrolysis – mEFTs acts to recharge mEFTu with GTP, and mEFG1 catalyzes the translocation of the ribosome along the mRNA to the next codon. The UAA or UAG mitochondrial stop codons are recognized by the MTRF1L release factor that acts to hydrolyse the peptidyl-tRNA bond and thereby liberate the completed polypeptide. Non-canonical release factors encoded by the mammalian MTRF1, C12orf65 and ICT1 genes are also thought to play a role in the termination step. Finally, the mitochondrial recycling factors mRRF1 and mRRF2 promote ribosomal dissociation and release of the deacylated tRNA and mRNA substrate.

As in mammals, flies have single copy genes encoding the initiation factors, mIF2 and mIF3, and the elongation factors mEFTs and EFG1 (). However, unlike mammals, flies have 2 distinct mEFTu proteins, one of which (mEFTu2) is enriched in the testis Citation33,34 (Supplementary Table 2). Of the fly mIFs and mEFs, only mEFG1 (encoded by the iconoclast gene) has been characterized to date.Citation68 Interestingly, it contains a nuclear localization sequence in addition to a mitochondrial targeting sequence, and may relay regulatory signals from the mitochondrion to the nucleus.Citation68

Table 2. D. melanogaster mitochondrial translation factors.

A single release factor-encoding gene, mRF1, exists in flies that is orthologous to the mammalian genes, MTRF1L and MTRF1 (). The fly orthologs of mammalian C12orf65 and ICT1 are CG30100 (44% amino acid identity) and CG6094 (39% identity), though these are omitted from the list of canonical factors presented here. Both mammalian and fly genomes harbor single copy genes encoding the 2 mitochondrial recycling factors, mRRF1 and mRRF2 (). None of these factors have been characterized in flies to date.

Conclusions

Translation factors have been studied in D. melanogaster for some 30 years, with many studies taking advantage of the tractability of this organism to probe gene function through genetic and phenotypic analyses. However, most of these investigations have focused on one or only a few translation factors. Prior to this report, several factors had not been clearly identified at all and a comprehensive and up-to-date overview was lacking. This survey identifies the full set of canonical translation factors in D. melanogaster and provides a systematic nomenclature for flies that is consistent with that used more broadly. In addition, we have improved the accuracy and quality of GO annotations of these factors – these improvements will directly assist the many studies that rely on such annotations to interpret data and guide research. Finally, we have compared the well-characterized set of mammalian translation factors to that in flies, and provided an overview of the published literature on the fly factors to date. This analysis reveals an expansion of certain translation factors compared to mammals, including a set of 11 testis-specific factors, indicating that specialized translation machinery operates in the male germline of D. melanogaster (also see ref.Citation9). (There is no evidence for a similar enrichment of specific translation factors in the female germline [Supplementary Table 2]).

Together, the information and annotation improvements reported herein will facilitate access to existing information on translation factors in flies and will aid further discoveries in the field. There are 3 areas in particular that would benefit from further study. First, it is apparent that ∼50% of translation factors (including the majority of mitochondrial translation factors) are uncharacterized at the molecular and genetic level in flies (). The study of these factors in the experimentally tractable fly system is likely to reveal new features of their canonical roles in a multicellular organism. Second, there are now many examples across species of ‘translation factors’ having non-translational functions, including several examples in flies such as: eIF3e promoting the neddylation of cullins Citation69; eIF3m effecting apoptosome activity Citation70,71; a role for eEF5 in autophagy regulation Citation59; and eEFγ regulating organelle transport along microtubules.Citation72 The fly is an ideal genetic system to discover and dissect such alternative roles. Finally, we are not aware of any fly models of human diseases associated with defective translation factors.Citation4-6 Given the high evolutionary conservation of these proteins, and the proven utility of modeling human disease in D. melanogaster,Citation73 including those associated with defects in other components of the translational machinery,Citation7 we hope and expect that this avenue of research will expand in the near future.

Disclosure of potential conflicts of interest

The authors declare no competing or financial interests.

Author contributions

S.J.M. and P.L. performed the analysis, H.A reviewed and revised GO annotations, S.J.M. prepared the manuscript, P.L. edited the manuscript.

Supplemental material

KFLY_A_1220464_Supplemental.zip

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Funding

S.J.M. and H.A. are supported by the FlyBase NIH/NHGRI grant U41HG000739 (N. Perrimon, Harvard University, PI; N.H. Brown, University of Cambridge, coPI). P.L. is supported by CIHR grants MOP-44050 and IOP-107945 and by NSERC Discovery Grant RGPIN-2014-06340.

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The translation factors of Drosophila melanogaster
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The Translation Factors of Drosophila melanogaster
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The translation factors of Drosophila melanogaster
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References

  • Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 2010; 11:113-27; PMID:20094052; http://dx.doi.org/10.1038/nrm2838
  • Dever TE, Green R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb Perspect Biol 2012; 4:a013706; PMID:22751155; http://dx.doi.org/10.1101/cshperspect.a013706
  • Christian BE, Spremulli LL. Mechanism of protein biosynthesis in mammalian mitochondria. Biochim Biophys Acta 2012; 1819:1035-54; PMID:22172991; http://dx.doi.org/10.1016/j.bbagrm.2011.11.009
  • Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I. Targeting the translation machinery in cancer. Nat Rev Drug Discov 2015; 14:261-78; PMID:25743081; http://dx.doi.org/10.1038/nrd4505
  • Boczonadi V, Horvath R. Mitochondria: impaired mitochondrial translation in human disease. Int J Biochem Cell Biol 2014; 48:77-84; PMID:24412566; http://dx.doi.org/10.1016/j.biocel.2013.12.011
  • Spilka R, Ernst C, Mehta AK, Haybaeck J. Eukaryotic translation initiation factors in cancer development and progression. Cancer Lett 2013; 340:9-21; PMID:23830805; http://dx.doi.org/10.1016/j.canlet.2013.06.019
  • Lu J, Marygold SJ, Gharib WH, Suter B. The aminoacyl-tRNA synthetases of Drosophila melanogaster. Fly (Austin) 2015; 9:53-61; PMID:26761199; http://dx.doi.org/10.1080/19336934.2015.1101196
  • Lasko P. The Drosophila melanogaster genome: translation factors and RNA binding proteins. J Cell Biol 2000; 150:F51-6; PMID:10908586; http://dx.doi.org/10.1083/jcb.150.2.F51
  • Marygold SJ, Roote J, Reuter G, Lambertsson A, Ashburner M, Millburn GH, Harrison PM, Yu Z, Kenmochi N, Kaufman TC, et al. The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol 2007; 8:R216; PMID:17927810; http://dx.doi.org/10.1186/gb-2007-8-10-r216
  • Attrill H, Falls K, Goodman JL, Millburn GH, Antonazzo G, Rey AJ, Marygold SJ, FlyBase Consortium. FlyBase: establishing a Gene Group resource for Drosophila melanogaster. Nucleic Acids Res 2016; 44:D786-92; PMID:26467478; http://dx.doi.org/10.1093/nar/gkv1046
  • Sasikumar AN, Perez WB, Kinzy TG. The many roles of the eukaryotic elongation factor 1 complex. Wiley Interdiscip Rev RNA 2012; 3:543-55
  • Jackson RJ, Hellen CU, Pestova TV. Termination and post-termination events in eukaryotic translation. Adv Protein Chem Struct Biol 2012; 86:45-93; PMID:22243581; http://dx.doi.org/10.1016/B978-0-12-386497-0.00002-5
  • Hu Y, Flockhart I, Vinayagam A, Bergwitz C, Berger B, Perrimon N, Mohr SE. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinformatics 2011; 12:357; PMID:21880147; http://dx.doi.org/10.1186/1471-2105-12-357
  • Aitken CE, Lorsch JR. A mechanistic overview of translation initiation in eukaryotes. Nat Struct Mol Biol 2012; 19:568-76; PMID:22664984; http://dx.doi.org/10.1038/nsmb.2303
  • Myrick KV, Dearolf CR. Hyperactivation of the Drosophila Hop jak kinase causes the preferential overexpression of eIF1A transcripts in larval blood cells. Gene 2000; 244:119-25; PMID:10689194; http://dx.doi.org/10.1016/S0378-1119(99)00568-5
  • Krauss V, Reuter G. Two genes become one: the genes encoding heterochromatin protein Su(var)3-9 and translation initiation factor subunit eIF-2gamma are joined to a dicistronic unit in holometabolic insects. Genetics 2000; 156:1157-67; PMID:11063691
  • Qu S, Cavener DR. Isolation and characterization of the Drosophila melanogaster eIF-2 α gene encoding the α subunit of translation initiation factor eIF-2. Gene 1994; 140:239-42; PMID:8144032; http://dx.doi.org/10.1016/0378-1119(94)90550-9
  • Ye X, Cavener DR. Isolation and characterization of the Drosophila melanogaster gene encoding translation-initiation factor eIF-2 β. Gene 1994; 142:271-4; PMID:8194763; http://dx.doi.org/10.1016/0378-1119(94)90273-9
  • Williams DD, Pavitt GD, Proud CG. Characterization of the initiation factor eIF2B and its regulation in Drosophila melanogaster. J Biol Chem 2001; 276:3733-42; PMID:11060303; http://dx.doi.org/10.1074/jbc.M008041200
  • Hernandez G, Vazquez-Pianzola P, Zurbriggen A, Altmann M, Sierra JM, Rivera-Pomar R. Two functionally redundant isoforms of Drosophila melanogaster eukaryotic initiation factor 4B are involved in cap-dependent translation, cell survival, and proliferation. Eur J Biochem 2004; 271:2923-36; PMID:15233788; http://dx.doi.org/10.1111/j.1432-1033.2004.04217.x
  • Carrera P, Johnstone O, Nakamura A, Casanova J, Jackle H, Lasko P. VASA mediates translation through interaction with a Drosophila yIF2 homolog. Mol Cell 2000; 5:181-7; PMID:10678180; http://dx.doi.org/10.1016/S1097-2765(00)80414-1
  • Dorn R, Morawietz H, Reuter G, Saumweber H. Identification of an essential Drosophila gene that is homologous to the translation initiation factor eIF-4A of yeast and mouse. Mol Gen Genet 1993; 237:233-40; PMID:8455559
  • Hernandez G, Lalioti V, Vandekerckhove J, Sierra JM, Santaren JF. Identification and characterization of the expression of the translation initiation factor 4A (eIF4A) from Drosophila melanogaster. Proteomics 2004; 4:316-26; PMID:14760701; http://dx.doi.org/10.1002/pmic.200300555
  • Hernandez G, Altmann M, Sierra JM, Urlaub H, Diez del Corral R, Schwartz P, Rivera-Pomar R. Functional analysis of seven genes encoding eight translation initiation factor 4E (eIF4E) isoforms in Drosophila. Mech Dev 2005; 122:529-43; PMID:15804566; http://dx.doi.org/10.1016/j.mod.2004.11.011
  • Hernandez G, Vazquez-Pianzola P. Functional diversity of the eukaryotic translation initiation factors belonging to eIF4 families. Mech Dev 2005; 122:865-76; PMID:15922571; http://dx.doi.org/10.1016/j.mod.2005.04.002
  • Hernandez G, Diez del Corral R, Santoyo J, Campuzano S, Sierra JM. Localization, structure and expression of the gene for translation initiation factor eIF-4E from Drosophila melanogaster. Mol Gen Genet 1997; 253:624-33; PMID:9065696; http://dx.doi.org/10.1007/s004380050365
  • Hernandez G, Sierra JM. Translation initiation factor eIF-4E from Drosophila: cDNA sequence and expression of the gene. Biochim Biophys Acta 1995; 1261:427-31; PMID:7742371; http://dx.doi.org/10.1016/0167-4781(95)00039-J
  • Cho PF, Gamberi C, Cho-Park YA, Cho-Park IB, Lasko P, Sonenberg N. Cap-dependent translational inhibition establishes two opposing morphogen gradients in Drosophila embryos. Curr Biol 2006; 16:2035-41; PMID:17055983; http://dx.doi.org/10.1016/j.cub.2006.08.093
  • Cho PF, Poulin F, Cho-Park YA, Cho-Park IB, Chicoine JD, Lasko P, Sonenberg N. A new paradigm for translational control: inhibition via 5′-3′ mRNA tethering by Bicoid and the eIF4E cognate 4EHP. Cell 2005; 121:411-23; PMID:15882623; http://dx.doi.org/10.1016/j.cell.2005.02.024
  • Yarunin A, Harris RE, Ashe MP, Ashe HL. Patterning of the Drosophila oocyte by a sequential translation repression program involving the d4EHP and Belle translational repressors. RNA Biol 2011; 8:904-12; PMID:21788736; http://dx.doi.org/10.4161/rna.8.5.16325
  • Ghosh S, Lasko P. Loss-of-function analysis reveals distinct requirements of the translation initiation factors eIF4E, eIF4E-3, eIF4G and eIF4G2 in Drosophila spermatogenesis. PLoS One 2015; 10:e0122519; PMID:25849588; http://dx.doi.org/10.1371/journal.pone.0122519
  • Hernandez G, Han H, Gandin V, Fabian L, Ferreira T, Zuberek J, Sonenberg N, Brill JA, Lasko P. Eukaryotic initiation factor 4E-3 is essential for meiotic chromosome segregation, cytokinesis and male fertility in Drosophila. Development 2012; 139:3211-20; PMID:22833128; http://dx.doi.org/10.1242/dev.073122
  • Brown JB, Boley N, Eisman R, May GE, Stoiber MH, Duff MO, Booth BW, Wen J, Park S, Suzuki AM, et al. Diversity and dynamics of the Drosophila transcriptome. Nature 2014; 512:393-9; PMID:24670639; http://dx.doi.org/10.1038/nature12962
  • Chintapalli VR, Wang J, Dow JA. Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nat Genet 2007; 39:715-20; PMID:17534367; http://dx.doi.org/10.1038/ng2049
  • Baker CC, Fuller MT. Translational control of meiotic cell cycle progression and spermatid differentiation in male germ cells by a novel eIF4G homolog. Development 2007; 134:2863-9; PMID:17611220; http://dx.doi.org/10.1242/dev.003764
  • Franklin-Dumont TM, Chatterjee C, Wasserman SA, Dinardo S. A novel eIF4G homolog, Off-schedule, couples translational control to meiosis and differentiation in Drosophila spermatocytes. Development 2007; 134:2851-61; PMID:17611222; http://dx.doi.org/10.1242/dev.003517
  • Hernandez G, del Mar Castellano M, Agudo M, Sierra JM. Isolation and characterization of the cDNA and the gene for eukaryotic translation initiation factor 4G from Drosophila melanogaster. Eur J Biochem 1998; 253:27-35; PMID:9578457; http://dx.doi.org/10.1046/j.1432-1327.1998.2530027.x
  • Takahashi K, Maruyama M, Tokuzawa Y, Murakami M, Oda Y, Yoshikane N, Makabe KW, Ichisaka T, Yamanaka S. Evolutionarily conserved non-AUG translation initiation in NAT1/p97/DAP5 (EIF4G2). Genomics 2005; 85:360-71; PMID:15718103; http://dx.doi.org/10.1016/j.ygeno.2004.11.012
  • Yoshikane N, Nakamura N, Ueda R, Ueno N, Yamanaka S, Nakamura M. Drosophila NAT1, a homolog of the vertebrate translational regulator NAT1/DAP5/p97, is required for embryonic germband extension and metamorphosis. Dev Growth Differ 2007; 49:623-34; PMID:17716306; http://dx.doi.org/10.1111/j.1440-169X.2007.00956.x
  • Bradley S, Narayanan S, Rosbash M. NAT1/DAP5/p97 and atypical translational control in the Drosophila Circadian Oscillator. Genetics 2012; 192:943-57; PMID:22904033; http://dx.doi.org/10.1534/genetics.112.143248
  • Liberman N, Marash L, Kimchi A. The translation initiation factor DAP5 is a regulator of cell survival during mitosis. Cell Cycle 2009; 8:204-9; PMID:19158497; http://dx.doi.org/10.4161/cc.8.2.7384
  • Kim JH, Park SM, Park JH, Keum SJ, Jang SK. eIF2A mediates translation of hepatitis C viral mRNA under stress conditions. EMBO J 2011; 30:2454-64; PMID:21556050; http://dx.doi.org/10.1038/emboj.2011.146
  • Parsyan A, Shahbazian D, Martineau Y, Petroulakis E, Alain T, Larsson O, Mathonnet G, Tettweiler G, Hellen CU, Pestova TV, et al. The helicase protein DHX29 promotes translation initiation, cell proliferation, and tumorigenesis. Proc Natl Acad Sci U S A 2009; 106:22217-22; PMID:20018725; http://dx.doi.org/10.1073/pnas.0909773106
  • Pisareva VP, Pisarev AV, Komar AA, Hellen CU, Pestova TV. Translation initiation on mammalian mRNAs with structured 5′UTRs requires DExH-box protein DHX29. Cell 2008; 135:1237-50; PMID:19109895; http://dx.doi.org/10.1016/j.cell.2008.10.037
  • Hernandez G, Miron M, Han H, Liu N, Magescas J, Tettweiler G, Frank F, Siddiqui N, Sonenberg N, Lasko P. Mextli is a novel eukaryotic translation initiation factor 4E-binding protein that promotes translation in Drosophila melanogaster. Mol Cell Biol 2013; 33:2854-64; PMID:23716590; http://dx.doi.org/10.1128/MCB.01354-12
  • Lefrere V, Vincent A, Amalric F. Drosophila melanogaster poly(A)-binding protein: cDNA cloning reveals an unusually long 3′-untranslated region of the mRNA, also present in other eukaryotic species. Gene 1990; 96:219-25; PMID:2125288; http://dx.doi.org/10.1016/0378-1119(90)90256-Q
  • Smith RW, Blee TK, Gray NK. Poly(A)-binding proteins are required for diverse biological processes in metazoans. Biochem Soc Trans 2014; 42:1229-37; PMID:25110030; http://dx.doi.org/10.1042/BST20140111
  • Ji Y, Shah S, Soanes K, Islam MN, Hoxter B, Biffo S, Heslip T, Byers S. Eukaryotic initiation factor 6 selectively regulates Wnt signaling and β-catenin protein synthesis. Oncogene 2008; 27:755-62; PMID:17667944; http://dx.doi.org/10.1038/sj.onc.1210667
  • Miluzio A, Beugnet A, Volta V, Biffo S. Eukaryotic initiation factor 6 mediates a continuum between 60S ribosome biogenesis and translation. EMBO Rep 2009; 10:459-65; PMID:19373251; http://dx.doi.org/10.1038/embor.2009.70
  • Palacios IM, Gatfield D, St Johnston D, Izaurralde E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 2004; 427:753-7; PMID:14973490; http://dx.doi.org/10.1038/nature02351
  • Frazer LN, Nancollis V, O'Keefe RT. The role of Snu114p during pre-mRNA splicing. Biochem Soc Trans 2008; 36:551-3; PMID:18482006; http://dx.doi.org/10.1042/BST0360551
  • Carmell MA, Xuan Z, Zhang MQ, Hannon GJ. The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev 2002; 16:2733-42; PMID:12414724; http://dx.doi.org/10.1101/gad.1026102
  • Lee S, Nahm M, Lee M, Kwon M, Kim E, Zadeh AD, Cao H, Kim HJ, Lee ZH, Oh SB, et al. The F-actin-microtubule crosslinker Shot is a platform for Krasavietz-mediated translational regulation of midline axon repulsion. Development 2007; 134:1767-77; PMID:17409115; http://dx.doi.org/10.1242/dev.02842
  • Dever TE, Gutierrez E, Shin BS. The hypusine-containing translation factor eIF5A. Crit Rev Biochem Mol Biol 2014; 49:413-25; PMID:25029904; http://dx.doi.org/10.3109/10409238.2014.939608
  • Gonzalez-Flores JN, Shetty SP, Dubey A, Copeland PR. The molecular biology of selenocysteine. Biomol Concepts 2013; 4:349-65; PMID:25436585; http://dx.doi.org/10.1515/bmc-2013-0007
  • Hovemann B, Richter S, Walldorf U, Cziepluch C. Two genes encode related cytoplasmic elongation factors 1 α (EF-1 α) in Drosophila melanogaster with continuous and stage specific expression. Nucleic Acids Res 1988; 16:3175-94; PMID:3131735; http://dx.doi.org/10.1093/nar/16.8.3175
  • Fan Y, Schlierf M, Gaspar AC, Dreux C, Kpebe A, Chaney L, Mathieu A, Hitte C, Gremy O, Sarot E, et al. Drosophila translational elongation factor-1gamma is modified in response to DOA kinase activity and is essential for cellular viability. Genetics 2010; 184:141-54; PMID:19841092; http://dx.doi.org/10.1534/genetics.109.109553
  • Grinblat Y, Brown NH, Kafatos FC. Isolation and characterization of the Drosophila translational elongation factor 2 gene. Nucleic Acids Res 1989; 17:7303-14; PMID:2508059; http://dx.doi.org/10.1093/nar/17.18.7303
  • Patel PH, Costa-Mattioli M, Schulze KL, Bellen HJ. The Drosophila deoxyhypusine hydroxylase homologue nero and its target eIF5A are required for cell growth and the regulation of autophagy. J Cell Biol 2009; 185:1181-94; PMID:19546244; http://dx.doi.org/10.1083/jcb.200904161
  • Hirosawa-Takamori M, Chung HR, Jackle H. Conserved selenoprotein synthesis is not critical for oxidative stress defence and the lifespan of Drosophila. EMBO Rep 2004; 5:317-22; PMID:14978508; http://dx.doi.org/10.1038/sj.embor.7400097
  • Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM, Yang L, Artieri CG, van Baren MJ, Boley N, Booth BW, et al. The developmental transcriptome of Drosophila melanogaster. Nature 2011; 471:473-9; PMID:21179090; http://dx.doi.org/10.1038/nature09715
  • Chao AT, Dierick HA, Addy TM, Bejsovec A. Mutations in eukaryotic release factors 1 and 3 act as general nonsense suppressors in Drosophila. Genetics 2003; 165:601-12; PMID:14573473
  • Nurenberg E, Tampe R. Tying up loose ends: ribosome recycling in eukaryotes and archaea. Trends Biochem Sci 2013; 38:64-74; PMID:23266104; http://dx.doi.org/10.1016/j.tibs.2012.11.003
  • Coelho CM, Kolevski B, Bunn C, Walker C, Dahanukar A, Leevers SJ. Growth and cell survival are unevenly impaired in pixie mutant wing discs. Development 2005; 132:5411-24; PMID:16291791; http://dx.doi.org/10.1242/dev.02148
  • Andersen DS, Leevers SJ. The essential Drosophila ATP-binding cassette domain protein, Pixie, binds the 40 S ribosome in an ATP-dependent manner and is required for translation initiation. J Biol Chem 2007; 282:14752-60; PMID:17392269; http://dx.doi.org/10.1074/jbc.M701361200
  • Schleich S, Strassburger K, Janiesch PC, Koledachkina T, Miller KK, Haneke K, Cheng YS, Kuchler K, Stoecklin G, Duncan KE, et al. DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth. Nature 2014; 512:208-12; PMID:25043021; http://dx.doi.org/10.1038/nature13401
  • Kuzmenko A, Atkinson GC, Levitskii S, Zenkin N, Tenson T, Hauryliuk V, Kamenski P. Mitochondrial translation initiation machinery: conservation and diversification. Biochimie 2014; 100:132-40; PMID:23954798; http://dx.doi.org/10.1016/j.biochi.2013.07.024
  • Trivigno C, Haerry TE. The Drosophila mitochondrial translation elongation factor G1 contains a nuclear localization signal and inhibits growth and DPP signaling. PLoS One 2011; 6:e16799; PMID:21364917; http://dx.doi.org/10.1371/journal.pone.0016799
  • Rencus-Lazar S, Amir Y, Wu J, Chien CT, Chamovitz DA, Segal D. The proto-oncogene Int6 is essential for neddylation of Cul1 and Cul3 in Drosophila. PLoS One 2008; 3:e2239; PMID:18493598; http://dx.doi.org/10.1371/journal.pone.0002239
  • Chew SK, Chen P, Link N, Galindo KA, Pogue K, Abrams JM. Genome-wide silencing in Drosophila captures conserved apoptotic effectors. Nature 2009; 460:123-7; PMID:19483676; http://dx.doi.org/10.1038/nature08087
  • D'Brot A, Chen P, Vaishnav M, Yuan S, Akey CW, Abrams JM. Tango7 directs cellular remodeling by the Drosophila apoptosome. Genes Dev 2013; 27:1650-5; PMID:23913920; http://dx.doi.org/10.1101/gad.219287.113
  • Serpinskaya AS, Tuphile K, Rabinow L, Gelfand VI. Protein kinase Darkener of apricot and its substrate EF1gamma regulate organelle transport along microtubules. J Cell Sci 2014; 127:33-9; PMID:24163433; http://dx.doi.org/10.1242/jcs.123885
  • Ugur B, Chen K, Bellen HJ. Drosophila tools and assays for the study of human diseases. Dis Model Mech 2016; 9:235-44; PMID:26935102; http://dx.doi.org/10.1242/dmm.023762
  • Qu S, Perlaky SE, Organ EL, Crawford D, Cavener DR. Mutations at the Ser50 residue of translation factor eIF-2alpha dominantly affect developmental rate, body weight, and viability of Drosophila melanogaster. Gene Expr 1997; 6:349-60; PMID:9495316
  • Miyazaki S, Rasmussen S, Imatani A, Diella F, Sullivan DT, Callahan R. Characterization of the Drosophila ortholog of mouse eIF-3p48/INT-6. Gene 1999; 233:241-7; PMID:10375641; http://dx.doi.org/10.1016/S0378-1119(99)00130-4
  • Lavoie CA, Lachance PE, Sonenberg N, Lasko P. Alternatively spliced transcripts from the Drosophila eIF4E gene produce two different Cap-binding proteins. J Biol Chem 1996; 271:16393-8; PMID:8663200; http://dx.doi.org/10.1074/jbc.271.27.16393
  • Okumura F, Zou W, Zhang DE. ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP. Genes Dev 2007; 21:255-60; PMID:17289916; http://dx.doi.org/10.1101/gad.1521607
  • Valzania L, Ono H, Ignesti M, Cavaliere V, Bernardi F, Gamberi C, Lasko P, Gargiulo G. Drosophila 4EHP is essential for the larval-pupal transition and required in the prothoracic gland for ecdysone biosynthesis. Dev Biol 2016; 410:14-23; PMID:26721418; http://dx.doi.org/10.1016/j.ydbio.2015.12.021
  • Shchedrina VA, Kabil H, Vorbruggen G, Lee BC, Turanov AA, Hirosawa-Takamori M, Kim HY, Harshman LG, Hatfield DL, Gladyshev VN. Analyses of fruit flies that do not express selenoproteins or express the mouse selenoprotein, methionine sulfoxide reductase B1, reveal a role of selenoproteins in stress resistance. J Biol Chem 2011; 286:29449-61; PMID:21622567; http://dx.doi.org/10.1074/jbc.M111.257600
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