Ms170400925Topic: Rna editing at various cancersAbstractRna editing affects thousand of genes. Applying a bioinformatic overture, we recognized beneficial global hypoediting of Alu repetitive elements in brain, prostate, lung, kidney, and testis tumors. We confirm this by experimental finding that was showing significantly reduced editing in Alu sequences within MED13 transcripts in brain tissues. There is some editing of specific recoding and noncoding sites, which includes cancer-related genes, a more complex picture emerged, with a gene-specific editing pattern in tumors vs. normal tissues. There are 3 enzymes which are involved in reducing level of editing mediating enzymes, ADAR, ADARB1, and ADARB2, in brain tumors. The most aggressive of brain tumors ,is the reduction of ADARB2 displaying a 99% decrease in ADARB2 RNA levels. Between normal and tumour specimens there are changes of miRNA which are located in regions of chromosomal instability Oncogenes is in central role Altered by epigenetic control. We suggest that A-to-I RNA editing may serve as an additional epigenetic mechanism relevant to cancer development Metastasis-related miRNAs have been identified in various malignancies, mainly from cell line and xenograft experiments Examples include breast cancer-IntroductionRna Editing.In eukaryote there is RNA Editing but in prokaryotes there Is no RNA Editing because in prokaryotes there is in space exon or intron in eukaryotes there are parts for decoding they are exon the parts which are non coding called intron. Introns which are previously known that there is no significant role but now by research it has proven that these intron sequence are playing very very vital role in RNA Editing.We are having Dna now from Dna we produce RNA . RNA contains intron and exon. Black regions which are present in introns. After processing we get only mature RNA from pre mature rna. This is scheme of. RNA transcription and. Modification.Now this is the kind of Rna splicing which is the removal of intron and adaption of exon only. RNA is to be modified in three different ways5 prime capping and 3 prime capping SplicingRNA editingAny kind of change in RNA sequence without splicing which changes the nucleotide sequence of RNA from DNA called rna Editing Changes we can observe during RNA edittingThe most common type is addition here is the example strand does not have uracil after the addition there are some uracil in the sequence uracil can be one or moreDeletion Deletion of uracil . deletion of thymine can also be a part of this The Editosome ComplexEditing by insertion or deletion.Modification There are four bases cytosine, thymine adenosine ,guanine in modification here we seeC———- uA———–IInosine is not one of the adenine bases but it is important it has the feature to find the bond between cytosine, uracil, adenine. This can be changed so this is called RNA editingWhat RNA Editing is doing for usEukaryotic cells are tiny cells they have limited no. Of genes they need to work a lot if it need to work properly it has to produce many varieties of proteins at a particular time. At a given time it produce many proteins it should have many genes so inside the cell it require 50’000 proteins to function we require 50’000 genes for accommodation of genes. Eukaryotic cells are very tiny to hold 50’000 genes so its impossible now they require to produce a technique so that the no. Of genes remain constant 1 gene ———– 1 protein1 gene produce I protein this is not enough for sustaining the life. It vary the expression by using RNA Editting. We produce 2 varieties of protein from one gene. Change in sequenceA————-IThis change gives the sequence this Is called guanine If there are 2 II it will be taken as 2 ggIt will give rise to protein not changing the no. Of the genes that’s why RNA editing is important Systematic academic review Alterations in genomic miRNA copy numbers and location Between normal and tumour specimens there are changes of miRNA which are located in regions of chromosomal instability (amplification, translocation or deletion).we locate a deletion, amplification, here are some examples in chronic B cell lymphocytic leukemia (B-CLL The miRNA cluster 15a/16-1 is located there is deleted genomic locus .Alterations in miRNA transcriptional regulationMiRNA genes have promoters which express the miRNA in a cell specific manner and drive high levels of oncogenes in cases of chromosomal translocation. The mir-142 gene, found at the breakpoint junction , which causes an aggressive B cell leukemia .due to strong up-regulation of a translocate MYC gene which was truncated at the first exon, it locate only four nucleotides.Many transcription factors regulate miRNA expression in a tissue-specific and disease state-specific fashion and some miRNAs are regulated by well-established tumour suppressor or oncogene pathways, such as TP53, MYC and RAS (reviewed in The miRNA and its transcriptional regulators can participate in complex feedback regulation loops.miRNA dysregulation has also been linked to changes in epigenetic regulation, such as the methylation status of miRNA genes, which results in alterations in their expression levels . Examples of methylated miRNAs include mir-127 in bladder cancer cells and mir-9-1 in breast cancer. miRNA cancer databaseThe development of miRNA microarrays, RT–PCR platforms and deep sequencing methodologies have resulted in an exponential acquisition of miRNA profiles. Some of the published miRNA profiles are available in the NCBI Gene Expression Omnibus, similarly to mRNA profiles (other resources include: However, there is no database or viewer that allows for cross-platform comparison of existing data. The database of editing sites reported by Levanon et al. (2004) was used to search for abnormal editing patterns in cancer tissuesReduced editing of ALU cell as compare to normal cellsWe analyze that there is reduce editing of ALU cell I’m brain tumor as compare to normal cell e.g we perform an experiment of Rt- pcr here we see that the no. Of RLU is reduced as compare to normal brain cell as there is 46 cDNA clones of brain tumor cells while 75 cDNA of normal cells. A. Reduced Editting of ALU cells comparisonHuman Brain normal BRAMY2,BRACE2,NIH_MGC_95,96,119 5413 538 1.70 1021a 3806Brain cancer NCI_CGAP_Brn67,NIH_MGC_19 1518 45 275Placenta normal PLACE1 1078 9 0.27 64Placenta cancer NIH_MGC_10,NIH_MGC_21 1696 23 166Testis normal TST,TESTI4, TESTI2, NIH_MGC_97 7307 126 0.048 881Testis cancer NIH_MGC_92, NT2RP2, NT2RP3 1873 20 103Kidney normal NIH_MGC_75 217 26 1.46 1014 166Kidney cancer NIH_MGC_14,58,89 861 5 30Lung normal NIH_MGC_77 399 23 3.3 1010 187Lung cancer NIH_MGC_18,68,69,77 2125 15 79Prostate normal NIH_MGC_83 334 24 2 103 125Prostate cancer NIH_MGC_40,60,91 361 8 51Muscle normal NIH_MGC_81 282 2 0.1 14Muscle cancer NIH_MGC_17 1170 1 6B. MouseMouse mammary cell line RIKEN full-length enriched, 10-d lactation,adult female mammary gland1138 8 2 104 31Mouse mammary cancer NCI_CGAP_Mam1,2,3,4,5,6 8248 8 26Tissue heterogeneityTissues are generally composed of multiple cell types, each cell has different gene expression program disease which alters the expression programme of the affected cell type and cell type composition. If we separate these effects in the profiling of heterogeneous tumour samples, it may be useful to profile tumour cell lines and individual cell types that may be present in a tumour sample,. Strikingly, we can prepare the profile of a human cancer by combining tumour cell line and fat profiles of human at equal ratio. This exercise shows that the MCF7 tumour cell line , expressed many of the miRNAs present in the predominant tumour-derived cell type and it highlight the need for individual cell type miRNA profiles.miRNAs as tumour suppressors and oncogenesWe use miRNA dysregulation as diagnostic tool, even if the particular miRNAs do not serve any regulatory function. Alternatively, miRNA dysregulation could drive tumorigenesis, through the roles miRNAs can adopt as tumour suppressors or oncogenes. miRNAs that are up- or down-regulated in malignancies are respectively referred to as oncogenic or tumour-suppressor miRNAs, sometimes even if there is no evidence for their causative role in tumorigenesis. Some of the most commonly dysregulated miRNAs are summarized in.Table 1. Some of the most common cancer-associated miRNAsmiRNATissue type specificityChromosomal locationPropertyMalignancylet-7familyUbiquitousMultiple members (chromosomes 3, 9, 11, 19, 21, 22)TSCLL, lymphoma , gastric , lung , prostate breast , ovarian , colon , leiomyoma , melanoma miR-15a/16-1clusterUbiquitous13q14.2TSCLL , lymphoma , multiple myeloma , pituitary adenoma , prostate , pancreatic miR-17-92familyUbiquitousMultiple members (chromosomes 7, 13, X)OGLymphoma , multiple myeloma , lung , colon , medulloblastoma , breast , prostate miR-21Ubiquitous17q23.1OGLymphoma, breast, lung, prostate, gastric, cervical, head and neck, colorectal, glioblastoma (for all: )miR-26aUbiquitous3p22.2 (–1)TSLymphoma , hepatocellular carci- 12q14.1 (?2)OGnoma , thyroid carcinoma Glioblastoma , miR-34a/b/cUbiquitous1p36.22 (a)TSCLL , lymphoma 11q23.1 (b) Pancreatic colon , neuroblastoma 11q23.1 (c) Glioblastoma miR-155Haematopoietic system21q21.3OGLymphoma (ie Burkitt’s, Hodgkin’s, non-Hodgkin’s) CLL , breast ,lung colon pancreatic miR-200/141familyEpithelial-specificMultiple members (chromosomes 1, 12)TSBreast , , renal clear cell carcinoma gastric , bladder OG/TSOvarian miR-205Epithelial-specific1q32.2TSProstate , bladder , breast , oesophageal OGOvarian miR-206Skeletal muscle-specific6p12.2TSRhabdomyosarcoma , breast miR-9Nervous system-specific1q22 (?1)TSMedulloblastoma , ovarian 5q14.3 (?2)OG/TS 15q26.1 (?3) Breast Functional studies performed in cancer cell lines or mouse models of various malignancies through Discussion:By the use of edit of Rna we can cure disease of cancer although it is brain tumor, cancer, lung cancer kidney cancer or anything else it’s the great use of technology. miRNA expression patterns have been linked to clinical outcomes, given that miRNAs modulate tumour behavior such as tumour progression and metastasis. Expression of let-7 is down-regulated in non-small cell lung cancer patients and is associated with poor prognosis , , . Advances in miRNA detection, such as ISH or RT–PCR, may allow miRNAs to be used as diagnostic and prognostic markers in the clinic.- Reference’sWe thank Hugo Horlings, Marc van de Vijver, Iddo Ben-Dov, Markus Hafner, Stacy Ugras and Samuel Singer for sharing their unpublished data, and Miguel Brown and Aleksandra Mihailovic for assistance with figure generation. We thank Markus Hafner, Kemal Akat and Neil Renwick for their help with editing the manuscript. TAF was partially supported by a Memorial Sloan–Kettering Cancer Center paediatric haematology/oncology fellowship. JIS is supported by the Deutsche Forschungsgemeinschaft. TT is an HHMI investigator and work in his laboratory was supported by NIH Grants Nos MH08442 and RC1CA145442 and the Starr Cancer Foundation Annu. Rev. Biochem. 71: 817–846.Bhalla, K.N. 2005. Epigenetic and chromatin modifiers as targetedtherapy of hematologic malignancies. J. Clin. Oncol. 23: 3971–3993.Blow, M., Futreal, P.A., Wooster, R., and Stratton, M.R. 2004. A surveyof RNA editing in human brain. Genome Res. 14: 2379–2387.Blow, M.J., Grocock, R.J., van Dongen, S., Enright, A.J., Dicks, E.,Futreal, P.A., Wooster, R., and Stratton, M.R. 2006. RNA editing ofhuman microRNAs. Genome Biol. 7: R27.Boulton, S.J. 2006. BRCA1-mediated ubiquitylation. Cell Cycle5: 1481–1486.Brusa, R., Zimmermann, F., Koh, D.S., Feldmeyer, D., Gass, P., Seeburg,P.H., and Sprengel, R. 1995. Early-onset epilepsy and postnatallethality associated with an editing-deficient GluR-B allele in mice.Science 270: 1677–1680.Ceballos, E., Munoz-Alonso, M.J., Berwanger, B., Acosta, J.C.,Hernandez, R., Krause, M., Hartmann, O., Eilers, M., and Leon, J.2005. Inhibitory effect of c-Myc on p53-induced apoptosis inleukemia cells. Microarray analysis reveals defective induction of p53target genes and upregulation of chaperone genes. Oncogene24: 4559–4571.Chen, C.X., Cho, D.S., Wang, Q., Lai, F., Carter, K.C., and Nishikura, K.2000. A third member of the RNA-specific adenosine deaminasegene family, ADAR3, contains both single- and double-stranded RNAbinding domains. RNA 6: 755–767.Cheng, C.K., Chow, L.W., Loo, W.T., Chan, T.K., and Chan, V. 2005.The cell cycle checkpoint gene Rad9 is a novel oncogene activatedby 11q13 amplification and DNA methylation in breast cancer.Cancer Res. 65: 8646–8654.Clutterbuck, D.R., Leroy, A., O’Connell, M.A., and Semple, C.A. 2005. Abioinformatic screen for novel A-I RNA editing sites reveals recodingediting in BC10. Bioinformatics 21: 2590–2595.Coons, S.W., Johnson, P.C., Scheithauer, B.W., Yates, A.J., and Pearl,D.K. 1997. Improving diagnostic accuracy and interobserverconcordance in the classification and grading of primary gliomas.Cancer 79: 1381–1393.Eisenberg, E., Nemzer, S., Kinar, Y., Sorek, R., Rechavi, G., and Levanon,E.Y. 2005. Is abundant A-to-I RNA editing primate-specific? Trends We apologize to those investigators whose work we could not cite due to space constraints.