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• W2801168210 abstract "RNA editing is a source of transcriptomic diversity, mainly in non-coding regions, and is found to be altered in cancer. In this issue of Cancer Cell, Peng et al. show that RNA editing events are manifested at the proteomic levels and are a source of cancer protein heterogeneity. RNA editing is a source of transcriptomic diversity, mainly in non-coding regions, and is found to be altered in cancer. In this issue of Cancer Cell, Peng et al. show that RNA editing events are manifested at the proteomic levels and are a source of cancer protein heterogeneity. The identification of mutations that contribute to malignant initiation or progression has been the focus of cancer research for decades. Clonal accumulation of somatic mutations, referred to as “driver mutations,” confer a selective growth advantage to the cancer cell and are key to its progression. These mutations draw the road map of tumor development, and characterizing them enables the identification of important genes that are vital for cancer biology and are a potential source of therapeutic targets. The rapid expansion in sequencing capacity facilitated the discovery of mutations at the genome scale through the sequencing of a massive number of samples. As a result, large-scale cancer sequencing projects such as The Cancer Genome Atlas (TCGA) led to the identification of genes with recurring somatic mutations. Such genes are prime candidates as cancer-driver genes. Traditionally, DNA mutations are considered to bear the sole responsibility for alterations in genomic information and are the focus of such cancer-genome projects. However, A-to-I RNA editing, in which genomically encoded adenosines are transformed and recognized as guanosines in the RNA sequence, is an endogenous and powerful means of creating inner transcriptome diversity that, unlike DNA mutations, does not leave traces on the genome and thus cannot be detected by the current DNA-focused approaches. In this issue of Cancer Cell, Peng et al. focus on this class of nucleotide changes in order to demonstrate their contribution to protein diversity in cancer (Peng et al., 2018Peng X. Xu X. Wang Y. Hawke D.H. Yu S. Han L. Zhou Z. Mojumdar K. Jeong K.J. Labrie M. et al.A-to-I RNA editing contributes to proteomic diversity in cancer.Cancer Cell. 2018; 33 (this issue): 817-828Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). The magnitude of A-to-I RNA editing is unprecedented, with millions of sites already identified in the human genome (Bazak et al., 2014Bazak L. Haviv A. Barak M. Jacob-Hirsch J. Deng P. Zhang R. Isaacs F.J. Rechavi G. Li J.B. Eisenberg E. Levanon E.Y. A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes.Genome Res. 2014; 24: 365-376Crossref PubMed Scopus (343) Google Scholar). In A-to-I substitution, an adenosine (A) is converted to inosine (I) by hydrolytic deamination. The consequence of the editing is an A-to-G transformation that can lead to codon changes (recoding) with respect to the original genomic sequence. A-to-I RNA editing is catalyzed by enzymes of the Adenosine deaminases acting on RNA (ADAR) protein family. These highly conserved essential enzymes contain two or three double-stranded RNA (dsRNA) binding domains and a catalytic deaminase domain. Accordingly, dsRNA is considered to be a prerequisite for editing by ADARs. In addition to modifying the RNA sequence, editing by ADAR of inverted repetitive elements that form dsRNA is required to prevent aberrant activation of the cytosolic innate immune system by endogenous sequences (Liddicoat et al., 2015Liddicoat B.J. Piskol R. Chalk A.M. Ramaswami G. Higuchi M. Hartner J.C. Li J.B. Seeburg P.H. Walkley C.R. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.Science. 2015; 349: 1115-1120Crossref PubMed Scopus (456) Google Scholar, Mannion et al., 2014Mannion N.M. Greenwood S.M. Young R. Cox S. Brindle J. Read D. Nellåker C. Vesely C. Ponting C.P. McLaughlin P.J. et al.The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.Cell Rep. 2014; 9: 1482-1494Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar). The heterogeneity introduced by this previously overlooked phenomenon can be exploited by tumor cells to promote cancer progression through a mechanism similar to that of DNA mutation, mainly by creating versions of proteins that either are inactive (or less active) as tumor suppressors or increase the activity of tumor promoters. An interesting predication is that, similar to DNA mutations, RNA editing can also serve as a source for neoantigens (Roth et al., 2018Roth S.H. Danan-Gotthold M. Ben-Izhak M. Rechavi G. Cohen C.J. Louzoun Y. Levanon E.Y. Increased RNA Editing May Provide a Source for Autoantigens in Systemic Lupus Erythematosus.Cell Rep. 2018; 23: 50-57Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) that can be targeted by the immune system (Figure 1). In addition, RNA editing can be also utilized by the tumor through its ability to create temporal diversity, which, unlike DNA mutations, does not leave mutation burdens in the genome for many generations of cells. This attribute can help facilitate the generation of chemotherapy-resistant cells. Indeed, analysis of the transcriptome of hundreds of tumor samples, mainly from the TCGA project, showed that RNA editing levels in most tumor types is significantly higher than those in matched normal tissue (Fumagalli et al., 2015Fumagalli D. Gacquer D. Rothé F. Lefort A. Libert F. Brown D. Kheddoumi N. Shlien A. Konopka T. Salgado R. et al.Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome.Cell Rep. 2015; 13: 277-289Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, Han et al., 2015Han L. Diao L. Yu S. Xu X. Li J. Zhang R. Yang Y. Werner H.M.J. Eterovic A.K. Yuan Y. et al.The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers.Cancer Cell. 2015; 28: 515-528Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, Paz-Yaacov et al., 2015Paz-Yaacov N. Bazak L. Buchumenski I. Porath H.T.T. Danan-Gotthold M. Knisbacher B.A.A. Eisenberg E. Levanon E.Y. Elevated RNA Editing Activity Is a Major Contributor to Transcriptomic Diversity in Tumors.Cell Rep. 2015; 13: 267-276Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). As is the case with somatic mutations in the DNA, most of such RNA modifications are likely to be “passengers” without effect, especially because the vast majority of these editing events are usually located within the noncoding Alu elements, the main ADAR targets in the human genome. However, significant differences between editing levels in several recoding sites, at which A-to-I editing results in non-synonymous substitutions in protein-coding sequences, were found as well. Some of these sites were already reported to play critical roles in tumorigenesis (Chen et al., 2013Chen L. Li Y. Lin C.H. Chan T.H.M. Chow R.K.K. Song Y. Liu M. Yuan Y.F. Fu L. Kong K.L. et al.Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma.Nat. Med. 2013; 19: 209-216Crossref PubMed Scopus (336) Google Scholar, Galeano et al., 2013Galeano F. Rossetti C. Tomaselli S. Cifaldi L. Lezzerini M. Pezzullo M. Boldrini R. Massimi L. Di Rocco C.M. Locatelli F. Gallo A. ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.Oncogene. 2013; 32: 998-1009Crossref PubMed Scopus (102) Google Scholar). Although it is clear how to identify RNA editing events from transcriptome data, it is more challenging to detect the outcome of editing at the proteome level. Hence, virtually all studies done so far to screen for editing alterations in humans were limited to RNA analysis. The degree to which the editing changes in the RNA actually led to modified proteins remained an open question. To explore this issue, Peng et al. used a dataset of previously known editing sites to computationally predict the new peptides that are expected to be translated as a result of the editing events. Next, they searched for these peptides in a mass spectrometry (MS) database that contains peptides from the same samples used in the TCGA project. Focusing on samples from breast, ovarian, and colorectal cancers, they found considerable numbers of edited peptides. Because they have the matched genomic and transcriptome data of the same samples, they could compare the contribution of somatic mutations and RNA editing on the translated proteins. Remarkably, they found that the impact of editing on proteomic diversity is of similar magnitude, or even higher, to that of somatic mutations. Because the input for this screen was a set of previously known editing sites, it is reasonable to assume that the actual contribution of editing to cancer diversity at the protein level is even greater. To demonstrate a causal relationship between RNA editing events and tumorigenesis, the authors chose one of the editing sites, located in the COPA transcript, which showed significant alterations in its editing levels across cancer samples and correlated with worse progression-free survival time. CRISPR/Cas9-mediated COPA knockout cells were then transfected with cDNAs of the wild-type COPA and its edited version. Experimental in vivo characterization showed that edited COPA significantly increased phenotypes that are associated with tumorigenesis, including cell viability, wound healing, migration, and invasion. These results indicated that editing at the COPA transcript could induce the development and migration of cancer cells, similar to driver somatic mutations. In summary, large-scale sequencing projects aim to identify all human cancer genes. Over the last few years, the discovery of novel genes containing driver mutations has slowed, implying that the list is nearing saturation. The findings from the current study suggest that plenty of additional A-to-I RNA sites that alter protein sequence still await discovery. A-to-I RNA Editing Contributes to Proteomic Diversity in CancerPeng et al.Cancer CellApril 26, 2018In BriefBy an integrated analysis of TCGA genomic data and CPTAC proteomic data, Peng et al. show that A-to-I RNA editing contributes to proteomic diversity in breast cancer through changes in amino acid sequences. The edited COPA protein increases proliferation, migration, and invasion of cancer cells in vitro. Full-Text PDF Open Archive" @default.
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• W2801168210 title "A-to-I RNA Editing: An Overlooked Source of Cancer Mutations" @default.
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