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  2. TABLE OF CONTENT 1. Introduction 2. Mechanisms Of RNA Editing 3. Functions Of RNA Editing 4. Recent Research On RNA Editing 5. Major strengths and weaknesses of RNA Editing 6. Future perspectives 7. Challenges in RNA Editing 8. Conclusion 9. References 2
  3. INTRODUCTION RNA editing (also RNA modification) is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. • It occurs in all organisms and is one of the most evolutionarily conserved properties of RNAs. • RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. • RNA editing is relatively rare and can affect the stability of RNAs and has been linked with human diseases. 3
  5. MECHANISMS OF RNA EDITING 1. SITE-SPECIFIC DEAMINATION EDITING A(adenosine) to I(inosine) double-stranded mechanism • occurs in viruses, humans C(cytidine) to U(uridine) and U to C • occurs in the chloroplast, plant mitochondria, and human genes. 2. GUIDE RNA-MEDIATED SITE-SPECIFIC INSERTION AND DELETION OF URIDINE U insertion /deletion • Occurs in Kinetoplasts(networks of circular DNA molecules present in mitochondria) 5
  6. SITE-SPECIFIC DEAMINATED EDITING Site-specific Deamination of Cytidine and Adenosine: Cytidine Uridine Cytidine deaminase Adenosine Inosine ADAR 6
  7.  Occur in APO-B Gene  Unedited Gene -APO-B 100 Protein ( Liver)  Edited Gene- APO-B 48 Protein ( Intestine )  Enzyme ADAR ( ds binding Domains)  Inosine can base pair with any nitrogenous base pair it may be A T C G  It detected as Guanosine during translation process.  This conversion acting on dsRNA 7
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  10. Guide RNA mediated site-specific insertion and deletion of uridine Guide RNA: It is part of degraded introns. • It is a small fraction of the RNA sequence That just comes out of the splicing of RNA. • Guide RNA guide the process of RNA editing In eukaryotes, that's why called guide RNA. Step by Step mechanism • Cleavage of RNA with endonuclease • Activity of TuTase and addition of uridine • Ligation of nick using ligase 10
  12. • Three mammalian ADAR genes (ADAR1–3) with common functional domains have been identified. • Deficiencies in the A→I RNA editing mechanism cause human diseases and pathophysiology. • RNA editing is a major mechanism, although reported exclusively in Eukaryotes. • RNA editing has been reported in Protozoa, plants, and mammals, nuclear, mitochondrial, chloroplast, and viral RNAs; mRNA, tRNA, and rRNA and not yet fungi or prokaryotes; • Researchers are now exploring a form of editing in prokaryotes and certain viruses. • A method has been developed by researchers for seeing the RNA editing procedure in real-time, the repaired strand emits green light, and even for the confirmation of repair mechanisms. • However, researches are still ongoing to elucidate key mechanisms of editing in various organisms. RECENT RESEARCH ON RNA EDITING 12
  13. Major strengths and weakness of RNA Editing Major strengths of RNA Editing 1. RE has been integrated into biological networks 2. Gene expression, 3. RNA editing better than DNA editing. 4. RNA editing is therefore considered to be less risky. Major weakness of RNA Editing 1. How RE activity is globally regulated is unknown. 2. Many editing sites in human transcriptomes remain to be discovered. 3. Monitoring of the global activity of RE in-vivo is rare. 13
  14. Future perspectives of RNA Editing 1. Description of physiological significance of particular editing events identified in tumor, neuronal tissues and brain or other specialized organ. 2. Molecular mechanisms on how RE affect the expression or functions of many genes through the alteration of codon, splice pattern, stability or localization of protein coding transcripts, modulation of regulatory RNA biogenesis and function. 3. Monitoring of global activity of RE in-vivo as a useful early biomarker for patient with disease. 4. Therapeutic applications. 14
  15. CHALLENGES IN RNA EDITING High-throughput sequencing-based approaches are being widely adopted to answer questions that require a genome-wide approach, such as • “How many miRNAs are edited?” or • “How many editing sites are there in the human brain?” or • “How many editing sites are there in plant mitochondria RNA?” • The physiological significance of recoding editing of newly discovered protein- coding genes needs to be identified. • We need to better understand the significance of the editing of noncoding repetitive RNAs of transposons and retrotransposons 15
  16. CONCLUSION • RNA editing alters RNA sequence without altering the sequence or integrity of genomic DNA. • RNA editing generates RNA and protein diversity in eukaryotes and results in specific amino acid substitutions, deletions, and changes in gene expression levels. • Adenosine-to-inosine RNA editing represents the most important class of editing in human and affects function of many genes. 16
  17. References 1. Chen, Y.-T., I. Y.-F. Chang, C.-H. Kan, Y.-H. Liu, Y.-P. Kuo, H.-H. Tseng, H.-C. Chen, H. Liu, Y.-S. Chang and J.-S. J. C. Yu (2020). "circRNAome Profiling in Oral Carcinoma Unveils a Novel circFLNB that Mediates Tumour Growth-Regulating Transcriptional Response." 9(8): 1868. 2. Hsiao, Y.-H. E., J. H. Bahn, Y. Yang, X. Lin, S. Tran, E.-W. Yang, G. Quinones-Valdez and X. J. G. r. Xiao (2018). "RNA editing in nascent RNA affects pre-mRNA splicing." 28(6): 812-823. 3. Porath, H. T., E. Hazan, H. Shpigler, M. Cohen, M. Band, Y. Ben-Shahar, E. Y. Levanon, E. Eisenberg and G. J. N. c. Bloch (2019). "RNA editing is abundant and correlates with task performance in a social bumblebee." 10(1): 1-14. 4. Small, I. D., M. Schallenberg‐Rüdinger, M. Takenaka, H. Mireau and O. J. T. P. J. Ostersetzer‐Biran (2020). "Plant organellar RNA editing: what 30 years of research has revealed." 101(5): 1040-1056. 5. Song, B., Y. Shiromoto, M. Minakuchi and K. J. W. I. R. R. Nishikura (2022). "The role of RNA editing enzyme ADAR1 in human disease." 13(1): e1665. 6. Tran, S. S., H.-I. Jun, J. H. Bahn, A. Azghadi, G. Ramaswami, E. L. Van Nostrand, T. B. Nguyen, Y.-H. E. Hsiao, C. Lee and G. A. J. N. n. Pratt (2019). "Widespread RNA editing dysregulation in brains from autistic individuals." 22(1): 25-36. 17

Editor's Notes

  1. When we are talking about RNA editing we are talking about Eukaryotes RNA editing is widely observed in eukaryotic organisms and their viruses. So, RNA editing done in Eukaryotes because Prokaryote has all coding region no need of RNA splicing and RNA editing
  2. Frame shift does not occur . Reading frame remains same Only specific codons nature changes .
  3. Cytidine Deaminase in the presence of H2O removes NH3 and we get Uridine molecule . As Inosine is not from 4 type of nucleotide Inosine can pair with any 4 bases because it has complement nature to form bond with any one of the 4 bases
  4. We have APO-B gene with 4564 codons. Last codon is UAA which codes for nothing acts as Termination codon. Middle of Mrna we have CAA codon position is 2153 codes for glutamine amino acid so gene for this Mrna is present in liver cells Mrna remains unedited ribosomes assembly and protein synthesis start charge Trna will bring to respect mrna according to the codons present in mrna when Trna meets the 2153 codon that is CAA it will bring glutamine amino acid and will go on and then finally translation is stop to UAA trna fails to bring amino acid as code for UAA TRANSLATION WILL STOP AND FROM THIS PROCESS WE GET APO-B 100 PROTEIN Now GENE for this mrna present in intestine cell RNA editing takes place Deamination occurs at 2153 position by enzyme cytidine deaminase we need other proteins these proteins assembled at editing site referred as editosome , editosome mediated the RNA editing process and converting cytidine into Uridine which convert the codon CAA to UAA now this code for nothing in the middle of RNA molecule we have termination codon now when translation starts on this edited RNA when protein translation machinery meets the UAA CODON IT WILL ACT as termination codon and trna fails to bring amino acid .translation is terminate and we get new kid pf protein that is APO=B 48 protein which is different from APO-b 100 protein has got all the sequences translated into proteins Which includes LDL receptor binding domain that has sequences from 3373 codon to 3393 codon, so APO-B lacks the LDL receptor biding domain Code differences in these 2 protein Deamination of Cytidine gets converted into Uridine
  5. A guide RNA (gRNA) is a piece of RNA that functions as a guide for RNA- or DNA-targeting enzymes, with which it forms complexes. Very often these enzymes will delete, insert or otherwise alter the targeted RNA or DNA. As introns is noncoding but play a vital role in RNA editing those degraded Introns sequences Step 1 1 of 2 RNA editing is the alteration process of the mRNA sequence after the DNA transcription. This creates a difference in the nucleotide sequence between the original DNA template and the synthesized RNA strand, as well as the amino acid sequence of the protein. Step 2 2 of 2 The unedited mRNA binds with the guide RNA through their complementary segments. With the template provided by the gRNA, the mRNA will undergo cleavage and alteration of its nucleotide sequence that is completely different from its unedited version. exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Restriction endonucleases are enzymes that recognise DNA sequences, scan the sequence and cleave the fragment around or within that sequence. DNA ligase, an enzyme that seals single-strand nicks in double-stranded DNA. Base pairing with unedited primary transcript with guide RNA or g-RNA which contains complementary seq to the region around insertion or deletion points After that the newly formed double stranded region is then involved by an editosome a large protein complex that catalyze the editing The editosome opens the transcript the first mismatched nucleotide and start inserting the uridines inserting uridine will base pair with guide RNA and insertion will continue as long as A OR G is present in the Guide RNA and will stop when a C or U is encountered. The inserted nucleotide seq cause translational frameshift and because of translation frame shift can lead to change in a final protein seq Translational frameshift DNA: GAT CTC AAA which transcribes to mRNA: CUA GAG UUU So, if we have a deletion of the adenine (A) out of GAT. Everything is going to shift. DNA: GTC TCA AA mRNA: CAG AGU UU
  6. RNA editing variation can be coupled with gene expression variation, the researchers focused on microRNAs, a class of small noncoding RNAs that can regulate gene expression by binding to complementary sequences in mRNAs and causing the bound mRNA molecules to be degraded
  7. the study of abnormal changes in body functions that are the causes, consequences, or concomitants of disease processes.
  8. Some of the most common types of biological networks are: Protein-protein interaction networks. Metabolic networks. Genetic interaction networks. Gene / transcriptional regulatory networks. Cell signalling networks Unlike DNA, RNA molecules are transient, lasting only days to weeks in a cell. Even if off-target editing occurs, the edited information doesn't last forever, for some research and clinical purposes, editing RNA is more effective or useful. A cell retains its DNA for life, and passes an identical copy to daughter cells as it duplicates, so any changes to DNA are relatively permanent Unlike DNA editing, which is permanent, the effects of RNA editing − including potential off-target mutations in RNA − are transient and are not inherited. RNA editing is therefore considered to be less risky.