Alternative titles; symbols
HGNC Approved Gene Symbol: EIF4G2
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:10,797,046-10,808,926 (from NCBI)
All eukaryotic cellular mRNAs are posttranscriptionally modified by the addition of a cap structure, m(7)GpppN (where N is any nucleotide), at the 5-prime terminus. Translation initiation is mediated by specific recognition of the cap structure by eukaryotic translation initiation factor 4F (eIF4F), a cap-binding complex. Eukaryotic initiation factor 4G (EIF4G; 600495) serves as the scaffold for formation of the eIF4F complex. Imataka et al. (1997) identified a human embryonic brain cDNA encoding a protein of 907 amino acids, termed p97, with 28% identity to the C-terminal two-thirds of EIF4G, a region that contains EIF4A (see 601102)- and EIF3 (see 602039)-binding sites. In vitro mutagenesis followed by transfection into Hela cells demonstrated that the start codon is a GTG.
Shaughnessy et al. (1997) independently cloned a mouse homolog of EIF4G, which they designated Eif4g2, by exon trapping from a mouse YAC spanning a site of viral integration found in myeloid leukemias of BXH2 mice. Northern blots using the mouse gene as a probe revealed that the gene is expressed ubiquitously in human tissues as a 4.6-kb transcript. Yamanaka et al. (1997) reported that the mouse and human EIF4G2 (which they termed NAT1) genes are 96% identical.
In a screen for genes involved in interferon gamma (IFNG; 147570)-induced apoptosis, Levy-Strumpf et al. (1997) identified EIF4G2 and named it DAP5 for 'death-associated protein 5.'
Imataka et al. (1997) used immunoprecipitation studies with HA- or FLAG-tagged proteins to show that p97 specifically binds to EIF4A and EIF3, but not to EIF4E (133440) in vitro. Transient transfection experiments showed that p97 suppressed both cap-dependent and independent translation, and that overexpression of p97 reduced overall protein synthesis. Imataka et al. (1997) suggested that p97 is a general repressor of translation that acts by forming translationally inactive complexes.
Pyronnet et al. (1999) demonstrated that MNK1 (MKNK1; 606724) interacts with the C-terminal region of p97. They hypothesized that p97 may block phosphorylation of eIF4E by sequestering Mnk1.
Levy-Strumpf et al. (1997) showed that while a fragment of DAP5 cDNA from the C-terminal region (encoding a 28-kD 'miniprotein') protected cells from IFNG-induced programmed cell death at low levels of expression, higher levels of expression were toxic. They proposed that the miniprotein may be a dominant-negative inhibitor of the essential DAP5 protein, and that DAP5 may play a specific role in apoptosis.
Yamanaka et al. (1997) found that NAT1 mRNA is edited at high levels by APOBEC1 (600130), creating multiple stop codons. They suggested that aberrant APOBEC1 editing of NAT1 mRNA may contribute to the potent oncogenesis induced by APOBEC1 overexpression in mice.
In stressed cells, a caspase (see CASP1; 147678)-cleaved DAP5/p86 isoform regulates cap-independent translation of various mRNAs via an internal ribosome entry site (IRES). Marash et al. (2008) showed that DAP5 also regulated cap-independent translation in unstressed cells. Knockdown of endogenous DAP5 in HeLa cells by short hairpin RNA induced substantial apoptosis during M phase that was associated with reduced translation of the antiapoptotic proteins BCL2 (151430) and CDK1 (CDC2; 116940). Cap-dependent translation was not inhibited in DAP5-knockdown cells. Marash et al. (2008) concluded that DAP5 maintains cell survival during mitosis by promoting cap-independent translation of prosurvival proteins.
Shestakova et al. (2023) noted that EIF4G2 promotes translation of mRNAs with long 5-prime leaders and upstream ORFs (uORFs) via reinitiation after uORF translation or by substituting for EIF4G1 to promote leaky scanning through the translated uORF after loss of EIF4G1. They found that the uORF in the dual-coding POLG (174763)/POLGARF (620759) mRNA, which encodes distinct POLG and POLGARF proteins in overlapping reading frames downstream of the uORF, made translation of both POLG and POLGARF reliant on EIF4G2. EIF4G2 enhanced both leaky scanning and reinitiation, and it appeared that ribosomes could acquire EIF4G2 during the early steps of reinitiation. Shestakova et al. (2023) concluded that EIF4G2 is a multifunctional scanning guardian that replaces EIF4G1 to facilitate ribosome movement but not ribosome attachment to mRNAs with uORFs, like POLG/POLGARF.
Shaughnessy et al. (1997) suggested that, based on synteny with mouse chromosomes, the human EIF4G2 gene maps to 11p15. Yamanaka et al. (1997) independently mapped the EIF4G2 gene to 11p15 by fluorescence in situ hybridization.
Imataka, H., Olsen, H. S., Sonenberg. N. A new translational regulator with homology to eukaryotic translation initiation factor 4G. EMBO J. 16: 817-825, 1997. [PubMed: 9049310] [Full Text: https://doi.org/10.1093/emboj/16.4.817]
Levy-Strumpf, N., Deiss, L. P., Berissi, H., Kimchi, A. DAP-5, a novel homolog of eukaryotic translation initiation factor 4G isolated as a putative modulator of gamma interferon-induced programmed cell death. Molec. Cell. Biol. 17: 1615-1625, 1997. [PubMed: 9032289] [Full Text: https://doi.org/10.1128/MCB.17.3.1615]
Marash, L., Liberman, N., Henis-Korenblit, S., Sivan, G., Reem, E., Elroy-Stein, O., Kimchi, A. DAP5 promotes cap-independent translation of Bcl-2 and CDK1 to facilitate cell survival during mitosis. Molec. Cell 30: 447-459, 2008. [PubMed: 18450493] [Full Text: https://doi.org/10.1016/j.molcel.2008.03.018]
Pyronnet, S., Imataka, H., Gingras, A.-C., Fukunaga, R., Hunter, T., Sonenberg, N. Human eukaryotic translation initiation factor 4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E. EMBO J. 18: 270-279, 1999. [PubMed: 9878069] [Full Text: https://doi.org/10.1093/emboj/18.1.270]
Shaughnessy, J. D., Jr., Jenkins, N. A., Copeland, N. G. cDNA cloning, expression analysis, and chromosomal localization of a gene with high homology to wheat eIF-(iso)4F and mammalian eIF-4G. Genomics 39: 192-197, 1997. [PubMed: 9027506] [Full Text: https://doi.org/10.1006/geno.1996.4502]
Shestakova, E. D., Tumbinsky, R. S., Andreev, D. E., Rozov, F. N., Shatsky, I. N., Terenin, I. M. The roles of eIF4G2 in leaky scanning and reinitiation on the human dual-coding POLG mRNA. Int. J. Molec. Sci. 24: 17149, 2023. [PubMed: 38138978] [Full Text: https://doi.org/10.3390/ijms242417149]
Yamanaka, S., Poksay, K. S., Arnold, K. S., Innerarity, T. L. A novel translational repressor mRNA is edited extensively in livers containing tumors caused by the transgene expression of the apoB mRNA-editing enzyme. Genes Dev. 11: 321-333, 1997. [PubMed: 9030685] [Full Text: https://doi.org/10.1101/gad.11.3.321]