Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy; [email protected] - [email protected] Published in Atlas Database: March 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/EEF1E1ID40409ch6p24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70858/03-2020-EEF1E1ID40409ch6p24.pdf DOI: 10.4267/2042/70858 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Keywords EEF1E1; eukaryotic translation elongation factor 1 Eukaryotic translation elongation factor 1 epsilon 1, epsilon 1; AIMP3; p18; Translation; Translation alias EEF1E1, is a protein-coding gene that plays a elongation factor; protein synthesis; cancer; role in the elongation step of translation. In oncogene; cancer marker particular, it is an auxiliary component of the macromolecular aminoacyl-tRNA synthase complex (MARS). Identity Its expression is found frequently altered in human Other names: P18, AIMP3, ARS-interacting cancer cells and it is considered a putative tumor multifunctional protein 3, Multisynthase Complex suppressor gene. Auxiliary Component P18, Elongation Factor P18 This review collects the data on DNA/RNA, the HGNC (Hugo): EEF1E1 protein encoded and the diseases where EEF1E1 is involved. Location: 6p24.3 Figure. 1. EEF1E1 gene and splicing variants/isoforms. The figure shows the locus on chromosome 6 of the EEF1E1 gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org) Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 387 EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) Cristiano L Two main alternative splicing transcript variants for DNA/RNA EEF1E1 were detected although several others were reported. Description In addition, it was speculated the presence of six EEF1E1 (eukaryotic translation elongation factor 1 protein isoforms, but only two are properly epsilon 1) was identified for the first time by Mao described, i.e. the isoform 1 of 174 residues and the and colleagues in 1998 (Mao et al, 1998). EEF1E1 is isoform 2 that counts 139 residues. a protein-coding gene that starts at 8,079,395 nt and The main characteristics of the alternative splicing ends at 8,102,595 nt from pter. It has a length of transcript variants are reported in Table.1. 23,201 bp, counts 5 exons, and the current reference The transcript variant 1 mRNA has reference sequence is NC_000006.12. sequence NM_004280.5 and it is 1047 bp long. The It is proximal to BLOC1S5 (biogenesis of lysosomal 5'UTR counts 27 nt, the CDS is extended from 28 to organelles complex 1 subunit 5, alias MUTED) 552 nt, while the 3'UTR covers the last 495 nt. gene. Read-through transcription exists between The transcript variant 2 mRNA has reference BLOC1S5 gene and EEF1E1 gene with forming the sequence NM_001135650.2 and it is 562 bp long. read-through transcript EEF1E1-BLOC1S5 (alias The 5'UTR counts 27 nt, the CDS is extended from EEF1E1-MUTED) that is a candidate for nonsense- 28 to 447 nt, while the 3'UTR covers the last 115 nt. mediated mRNA decay (NMD) and it is unlikely to Pseudogene produce a protein product (He et al, 2018). Near to the genomic sequence of EEF1E1 there is a According to Entrez Gene, the analysis of the human strong promoter transcriptional element that is genome revealed the presence of an EEF1E1-related located at +1.0 kb. Enhancer transcriptional elements pseudogene on chromosome 2. This pseudogene was are located at +22.0 Kb and at +18.1 Kb respectively. appointed as eukaryotic translation elongation factor 1 epsilon 1 pseudogene 1, alias EEF1E1P1 and it is Transcription classified as a processed pseudogene Alternative splicing for EEF1E1 brings to multiple (http://www.ensembl.org/index.html). Its gene ID is transcript variants. In addition, a read-through 100130388, its reference is NC_000002.12, and its transcription is known between EEF1E1 and the location is 2q13. EEF1E1P1 starts at 111,887,890 nt neighboring downstream MUTED (muted homolog) and ends at 111,889,485 nt with a length of 1,596 nt. gene. MW Varian Exon Lengh Isofor Lengh Name RefSeq (1) Transcript ID Type Alias RefSeq (2) (kDa pI t s t (bp) m t (aa) ) protei EEF1E1 ENST00000488226. n - - 2 443 - - - 94 (?) (?) -001 2 codin g protei EEF1E1 ENST00000379715. n isoform O43324 19.8 8.5 Var.1 NM_004280.5 4 1077 NP_004271.1 174 -002 5 codin 1 -1 1 5 g protei EEF1E1 ENST00000507463. n 16.6 - - 3 654 - - - 150 (?) -003 1 codin 9 g protei EEF1E1 NM_001135650 ENST00000429723. n isoform O43324 NP_001129122 15.5 7.9 Var.2 4 562 139 -004 .2 2 codin 2 -2 .1 5 5 g protei EEF1E1 ENST00000502429. n - - 4 591 - - - 136 (?) (?) -005 1 codin g protei EEF1E1 ENST00000515633. n - - 3 460 - - - 56 5.89 (?) -006 1 codin g Table.1 Alterative splicing variants and isoforms of EEF1E1. (reworked from http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; https://web.expasy.org/protparam/; https://www.uniprot.org). ncRNA = non-coding RNA; nonsense md = nonsense mediated decay; (?) = undetermined; MW = molecular weight; pI = theoretical pI. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 388 EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) Cristiano L Figure.2 eEF1E1 protein. Graphical representation of eEF1E1 protein isoforms with the evidence of the main verified post- translational modifications (reworked from http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; http://bioinf.umbc.edu/dmdm/gene_prot_page.php). It virtually encodes a non-coding transcript of 430 bp characterized followed by a linker domain, while the named EEF1E1P1-201 (Ensembl Ref: major differences between the two isoforms are in ENST00000446998.2). The real presence of this the carboxyl half terminal. In fact, in the carboxyl transcript and its possible role in the cell are totally half terminal of isoform 1 there are reported two unknown. domain overlapping, i.e. a Glutathione S-transferase If EEF1E1P1 has any regulatory role in the C-terminal-like domain (GST_C_AIMP3), folded in expression of the respective gene as described for alpha-helical, and a more general and not well others (Hirotsune et al., 2003), is only speculation in characterized C-terminal domain. the absence of experimental evidence. Currently, In isoform 2, there is a unique region called C- there is no evidence about the involvement of this terminal domain of the Glutathione S-transferase pseudogene in human cancers or in other diseases. family (GST_C_family). The fold of this domain is alpha-helical (see figure.2). Protein EEF1E1 interacts with other members of the MARS complex and one interactional model was proposed Description (Mirande, 2017) although its exact interactions need The eukaryotic translation elongation factor 1 to be still clarified. epsilon 1 (alias eEF1E1, p18, AIMP3) is the smallest Post-translational modifications. Some post- component of the Multiaminoacyl-tRNA Synthetase translational modifications are observed, such as complex (alias MARS). The exact position of phosphorylation and acetylation EEF1E1 in the MARS complex is still unknown. (https://www.ncbi.nlm.nih.gov). However, it seems to be localized on the surface of the MARS complex and it seems to interact with the Expression eEF1H complex (Deineko V.V., 2008). eEF1E1 is expressed widely in human tissues and EEF1E1 is a small globular protein with a length of normal cells (https://www.genecards.org; 174 amino acids and a molecular weight of 19,8 kDa. https://www.proteinatlas.org/ENSG00000124802- eEF1E1 shows strong sequence similarity with EEF1E1/tissue) while its expression is altered in eukaryotic translation elongation factor 1 beta 2 ( many cancer types. Frequently it is downregulated in EEF1B2) and eukaryotic translation elongation various cancer tissues (Park et al, 2005). factor 1 gamma ( EEF1G) (Quevillon and Mirande, Cells that show overexpression of eEF1E1 show an 1996) and with the N-terminal sequence of valyl- acceleration of senescence and also defects in tRNA synthetase (Deineko V.V., 2008). nuclear morphology (Oh et al, 2010). eEF1E1 shows many domains in both isoforms: the amino half terminal is unique for both isoforms and Localisation shows an N-terminal-like domain not well EEF1E1 is located mostly in the cytoplasm but it was also found in the nucleus. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 389 EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) Cristiano L Figure 3. Cellular localization of eEF1E1(p18). In the figure is reported the cellular localization of eEF1E1 obtaining by immunofluorescent staining (antibody HPA027901). In particular, eEF1E1 shows to be localized both in cytosol and nucleoplasm in (1) A-431 cell line and (2) U-2 OS cell line. In green: antiboy for eEF1E1; In red: microtubules (reworked from https://www.proteinatlas.org/ ENSG00000124802-EEF1E1/cell) Function Other functions (non-canonical roles): in addition to what has already been said, it seems to play a role in It is well known that in eukaryotic cells the various embryonic development of the mammalian face components of translation machinery are properly and other structures (Fowles et al, 2003). organized into two main multienzyme structures: eEF1E1 has the ability to translocate into the nucleus eEF1H (macromolecular eukaryotic translation in response to DNA damage where it has a role in elongation factor-1 complex), formed by the the DNA damage response in association with translation elongation factors (EEF1B2, EEF1D, serine/threonine kinases ATM / ATR and TP53. In EEF1G) and VARS (valyl-tRNA synthetase), and fact, it was found a positive relationship between MARS (Multiaminoacyl-tRNA Synthetase complex expression levels of eEF1E1 and TP53, i.e.