Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Solid Tumour Section Short Communication

EEF1G/PPP6R3 (11q12-13) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy. [email protected] - [email protected]

Published in Atlas Database: May 2019 Online updated version : http://AtlasGeneticsOncology.org/Tumors/EEF1G_PPP6R3ID6948.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70700/05-2019-EEF1G_PPP6R3ID6948.pdf DOI: 10.4267/2042/70700 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

this cancer type are t(7;11)(q21;q13) Abstract CCDC132/PPP6R3, t(7;11)(q34;q13) Analysis of the EEF1G/PPP6R3 fusion involving PPP6R3/MGAM, t(7;11)(q34;q13)SSBP1/PPP6R3, EEF1G (alias, eukaryotic elongation and fusion PPP6R3/ARHGAP1, factor 1 gamma) and PPP6R3 (alias, PPP6R3/CNTN5, and PPP6R3/LRP5 (Yoshihara et phosphatase 6 regulatory subunit 3) gene. It was al., 2015; Hammerman et al., 2012; detected in lung squamous cell carcinoma. http://www.tumorfusions.org) Keywords Prognosis 11; EEF1G; eukaryotic translation There is no evidence of the impact of the elongation factor 1 gamma; EF1G, GIG35, EEF1G/PPP6R3 fusion gene on the tumour PRO1608, EEF1 gamma, EEF-1B gamma, EF-1- behaviour and so its contribution in the prognosis of gamma, elongation factor 1-gamma, translation lung squamous cell carcinoma is still unknown. elongation factor EEF-1 gamma chain, pancreatic tumor-related protein; PPP6R3, protein phosphatase Genes involved and 6 regulatory subunit 3, PP6R3, open reading frame 23, C11orf23, SAPS domain family member 3, SAPS3, EEF1G/PPP6R3, lung squamous cell carcinoma EEF1G Location 11q12.3 Clinics and pathology Note Disease Eukaryotic translation elongation factor 1 gamma, alias eEF1G, is a protein that play a main function in Lung squamous cell carcinoma the elongation step of translation process but also Note cover numerous moonlighting roles. Lung squamous cell carcinoma (lung SqCC) shows It is expressed ubiquitously in human tissues and very complex genomic alterations with abundant often it is found over-expressed in human cancer exonic mutations, genomic rearrangements and gene samples and cancer cell lines. copy number alterations. DNA / RNA Some authors detected the presence of the EEF1G (Eukaryotic Translation Elongation Factor 1 EEF1G/PPP6R3 fusion deriving by the genomic Gamma) is a protein coding gene with 10 exons and translocation of a part of EEF1G gene with a portion a length of 14388 bp (RefSeq NC_000011.10). Its of PPP6R3 gene, both located on chromosome 11 transcript is 1446 bp long (RefSeq NM_001404.5) (Hammerman et al., 2012). Other fusion genes or but was observed five splice variants and nine abnormal chromosomal translocations detected for pseudogenes probably originated by PPP6R3 in retrotransposition.

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(4) 185 EEF1G/PPP6R3 (11q12-13) Christiano L

Protein (RefSeq NC_000011.10) and with an abundant eEF1G is formed by 437 amino acids (RefSeq number of alternative splicing variants, i.e. 38 NP_001395.1), it has a molecular weight of 50.12 coding mRNA and 24 non-coding mRNA. kDa and it is a multi-domain protein which consist Protein of three main domains: from the amino to carboxyl PPP6R3 counts 24 protein isoforms and is one of the half terminal there are a glutathione S-transferase three regulatory subunits of protein phosphatase 6 (GST)-like N-terminus domain (NT-eEF1G), a (PP6) complex (York et al., 2014; Guergnon et al., glutathione S-transferase (GST)-like C-terminus 2009) and has a sit4-associated protein domain, alias domain (CT-eEF1G) and a conserved C-terminal SAPS domain (Stefansson and Brautigan, 2006). It domain (CD-eEF1G)(Achilonu et al.,2014). plays a role, as member of PP6 holoenzyme, in the eEF1G is a subunit of the eukaryotic elongation turnover of serine and threonine phosphorylation factor-1 complex named eEF1H that result by the events during mitosis acting as a regulatory element aggregation of different proteins that play a central of the complex. role in peptide elongation during eukaryotic protein biosynthesis. The physiological role of eEF1G is still Result of the chromosomal not well defined, however eEF1G seems to be necessary for guarantee the stability to entire eEF1H anomaly complex and to stimulate the activity of the eEF1B2 subunit during the elongation step of translation Hybrid Gene (Mansilla et al., 2002). However, are known that it The result of chromosomal anomaly is the has multiple non-canonical roles (moonlighting EEF1G/PPP6R3 fusion with the formation of a novel roles) inside the cell such as the interaction with but not still characterized fusion gene 5' EEF1G - 3' cytoskeleton and binding with various mRNA and PPP6R3. Hammerman and colleagues several proteins, comprise membrane-bound (Hammerman et al., 2012) found it in patients with receptors (Coumans et al., 2014; Corbi et al., 2010; lung squamous cell carcinoma (lung SqCC), but Cho et al., 2003). there are no data or evidence about its mRNA and/or PPP6R3 its protein. So, in this review, with the use of Ensembl (http://www.ensembl.org), will be Location 11q13.2 predicted the result of this rearrangement. However, DNA / RNA the data collected and showed are hypothesis and PPP6R3 is a protein coding gene of 154617 nt long have to be experimentally verified.

Figure 1. Schematic representation of the EEF1G gene, PPP6R3 gene and the EEF1G-PPP6R3 fusion. [A] In the upper side of the picture there are the genomic sequences of EEF1G and PPP6R3 genes with the indication of DNA breakpoints individuated by Hammerman and colleagues (Hammerman et al., 2012); [B] in the bottom side of the picture are reported the genomic rearrangement on chromosome 11 and the predicted structure of the novel EEF1G/PPP6R3 fusion after the analysis with Ensembl (http://www.ensembl.org). In addition, there are also indicated the promoter/enhancer elements (reworked from https://www.genecards.org).

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EEF1G/PPP6R3 (11q12-13) Christiano L

Description kind of tumors as EEF1G that is involved in A EEF1G/PPP6R3 fusion was found in lung numerous genomic alterations such as translocations squamous cell carcinoma (lung SqCC) and in novel fusion genes. Both genes are important (Hammerman et al., 2012). Hammerman and for cell biology and it is normal that they are colleagues (Hammerman et al., 2012) identified two subjected to rearrangements in cancer cells. In DNA breakpoints that cause the EEF1G/PPP6R3 addition, this could happens also for the fusion: the first is located at the position 62,323,148 characteristics of their promoters because at least for of the EEF1G gene, while the second is located at the PPP6R3 it is known that it possess a potent promoter position 68,368,269 of PPP6R3 (alias, SAPS3) gene, activity (Guo et al., 2016). However, the truly both upstream of the respective genes involved. In oncogenic potential of EEF1G/PPP6R3 in addition, Hammerman and colleagues (Hammerman proliferation and cancer aggressiveness needs to be et al., 2012) identified a novel fusion gene 5'EEF1G better elucidated. - 3'PPP6R3 derived by this abnormal translocation thus formed: at 5' fusion end there is a sequence References starting from 4 kb before EEF1G gene while at 3' Achilonu I, Siganunu TP, Dirr HW. Purification and fusion end there is a sequence starting from 303 bp characterisation of recombinant human eukaryotic after exon 19 of PPP6R3 gene. However, the elongation factor 1 gamma. Protein Expr Purif. 2014 nucleotide sequence of this novel chimeric gene is Jul;99:70-7 not reported or registered anywhere and so it remains Cho DI, Oak MH, Yang HJ, Choi HK, Janssen GM, Kim KM. uncharacterized. Direct and biochemical interaction between dopamine D3 receptor and elongation factor-1Bbetagamma. Life Sci. From the direct analysis of the gene sequences and 2003 Oct 24;73(23):2991-3004 the respective DNA breakpoints using Ensembl (http://www.ensembl.org), could be advanced the Corbi N, Batassa EM, Pisani C, et al. The eEF1γ subunit contacts RNA polymerase II and binds vimentin promoter hypothesis that the chromosomal rearrangement region. PLoS One. 2010 Dec 31;5(12):e14481 where EEF1G and PPP6R3 are involved, although it was described as an intra-chromosomal Coumans JVF, Gau D, Poljak A, Wasinger V, Roy P, Moens P. Green fluorescent protein expression triggers proteome translocation, it seems more similar to an inversion. changes in breast cancer cells Exp Cell Res 2014; 320(1): Moreover the first breakpoint is located 236,453 nt 33-45 before EEF1G gene while the second breakpoint is Guergnon J, Derewenda U, Edelson JR, Brautigan DL. located just before PPP6R3 gene, i.e. 92,441 nt Mapping of protein phosphatase-6 association with its before PPP6R3 gene (Figure.1). This chromosomal SAPS domain regulatory subunit using a model of helical rearrangement permits to bring near EEF1G to repeats BMC Biochem 2009; 10:24 PPP6R3, reducing the long distance between them, Guo R, Wang X, Chou MM, et al. PPP6R3-USP6 i.e. from 5,886,730 nt (about 5,886 kb) to only Amplification: Novel Oncogenic Mechanism in Malignant 328,894 nt (about 328 kb). The reason of this Nodular Fasciitis Genes Cancer 2016; 55:640-649 rearrangement is unknown. Hammerman PS, Lawrence MS, Voet D, et al. Transcript Comprehensive genomic characterization of squamous cell There is no evidence about the mRNA of the lung cancers Nature 2012; 489(7417):519-25 EEF1G/PPP6R3 fusion gene or other transcript Mansilla F, Friis I, Jadidi M, et al. Mapping the human resulting from the EEF1G/PPP6R3. translation elongation factor eEF1H complex using the yeast two-hybrid system. Biochem J 2002; 365(Pt 3):669- Fusion Protein 76 Description Stefansson B, Brautigan DL. Protein phosphatase 6 subunit There is no evidence of protein from the with conserved Sit4-associated protein domain targets IkappaBepsilon J Biol Chem 2006; 281(32):22624-34 EEF1G/PPP6R3 fusion gene. York A, Hutchinson EC, Fodor E. Interactome analysis of Oncogenesis the influenza A virus transcription/replication machinery The role in oncogenesis of the EEF1G/PPP6R3 identifies protein phosphatase 6 as a cellular factor required fusion is unclear, and there is no evidence about its for efficient virus replication J Virol. 2014 Nov;88(22):13284- effective transcription and/or translation. 99 Hammerman and colleagues (Hammerman et al., Yoshihara K, Wang Q, Torres-Garcia W, et al. The 2012) have supposed the presence of a fusion gene landscape and therapeutic relevance of cancer-associated 5'EEF1G - 3'PPP6R3 but actually there are poor data transcript fusions Oncogene 2015; 34(37):4845-54 about it and thus it is unclearly the role of this fusion This article should be referenced as such: gene, i.e. if is effectively translated into a functional Cristiano L. EEF1G/PPP6R3 (11q12-13). Atlas Genet protein or instead it plays a regulatory role. What it Cytogenet Oncol Haematol. 2020; 24(4):185-187. is clear is that PPP6R3 is involved in many and heterogeneous genomic translocations in different

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