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RNA structure and functions Dr. Rana M. W. Hasanato*, Dr. Sayed S. Al-Esawy** *Consultant, Clinical Biochemistry **Specialist, Medical Biochemistry College of Medicine and King Khalid University Hospital ---------------------RNA is a polymer composed of alternating units of ribonucleotides connected through a 3’-5’ phosphodiester bond. RNA can be single stranded (retroviruses ,HIV) , double stranded (reoviruses) or loop RNA STRUCTURE OF RNA: Three major types of RNA participate in the process of protein synthesis: - transfer RNA (tRNA) - messenger RNA (mRNA) - ribosomal RNA (rRNA) • In eukaryotes, small RNA molecules found in the nucleus (snRNA) are important for the posttranscriptional modifications of mRNA. The bases in RNA are: - adenine (A), guanine (G), cytosine (C), uracil (U). Like DNA, the three major types of RNA are forms of nucleic acid found in the cells and unbranched polymeric molecules composed of mononucleotides joined together by phosphodiester bonds. Unlike DNA, They differ as a group from DNA in several ways: o they are considerably smaller than DNA. o they contain ribose instead of deoxyribose and uracil instead of thymine. o most RNAs exist as single stranded entity that are capable of folding into complex structures. The three major types of RNA differ from each other In size, function, and special structural modifications. 1 A. Ribosomal RNA: rRNA is a type of RNA that is a component of ribosomes and plays a role in the process of translation (making protein from nucleic acid sequence). Ribosomal RNAs (rRNAs) are found in association with several proteins as components of the ribosomes-the complex structures that serve as the sites for protein synthesis. There are four rRNA size species (28S. 18S. 5.8S. and 5S) in the eukaryotic cytosol. rRNAs species make up 80% of the total RNA in the cell. B. Transfer RNA: tRNAs are RNA molecules that assists in decoding the information contained within mRNA during translation by recruiting the correct amino acid to the growing peptide chain. One end of the tRNA contains a three nucleotide sequence called the anticodon loop that is complementary to the codon of the mRNA. The other end of the tRNA is covalently attached to a specific amino acid. Transfer RNAs (tRNAs), the smallest of the three major species of RNA molecules (4S), have between 74 and 95 nucleotide residues. tRNAs species make up about 15 % of the total RNA in the cell. The tRNA molecules contain unusual bases e.g. dihydrouracil, and have extensive intrachain base-pairing. Each tRNA serves as an 'adaptor" molecule that carries its specific amino acid-covalently attached to its 3’ end-to the site of protein synthesis. C. Messenger RNA : Messenger RNAs are RNA molecules that carry the genetic information "message" from the DNA to the ribosomes to be translated into protein. The "message" in mRNA is carried in groups of three nucleotides called codons. Each codon specifies one amino acid in a protein according to the rules of the genetic code. 2 Messenger RNA (mRNA) comprises only about 5 % of RNA in the cell. It is the most heterogeneous type of RNA in size (500 to 6000 nucleotides) and base sequence. The mRNA carries genetic information from the nuclear DNA to the cytosol where it is used as the template for protein synthesis. Special structural characteristics of eukaryotic mRNA (but not prokaryotic) include a long sequence of adenine nucleotides (a 'poly-A tail) on the 3’ -end of the RNA chain plus a 'cap' on the 5’ -end consisting of a molecule of 7-methylguanosine attached 'backward' (5'5') through a triphosphate linkage. TRANSCRIPTION: RNA is synthesized as a complementary strand to one of the DNA strands as a template strand by the action of the enzyme RNA polymerase that reads the template strand in the 3’ 5’ direction and synthesizes RNA in the 5’ 3’. It utilizes the ribonucleoside triphosphate as a building units. The other DNA strand is called coding strand. A given strand may serve as template strand for genes and coding for the other. A central feature of transcription is that it is highly selective. For example many transcripts are made of some regions of the DNA. In another regions, few or no transcripts are made. This selectivity is due, at least in part, to signals embedded in the nucleotide sequence of DNA.These signals instruct the RNA polymerase where to start, how often to start, and where to stop transcription. Another important feature of transcription is that many RNA transcripts that initially are faithful copies of one of the two DNA strands may undergo various modifications, such as terminal additions, base modifications, trimming, and internal segment removal, followed by splicing, which convert the inactive primary transcript into a functional molecule. The structure of RNA polymerase, the signals that control transcription and the varieties of modification that RNA transcripts can differ among organisms and particularly from prokaryotes to eukaryotes. 3 RNA POLYMERASES: They are RNA-dependant RNA polymerases, i.e. they add (U) in the newly synthesized strand for (A) in the template strand. A) Prokaryotic: RNA polymerase is a multisubunit enzyme that makes RNA using DNA as a template and then recognizes the end of the DNA sequence to be transcribed (the termination region).. It uses the nucleoside triphosphates, ATP, GTP, CTP, and UTP to make a complementary RNA copy of the DNA template strand. The nucleoside bases adenine, guanine, cytosine and uracil pair with the bases thymine, cytosine, guanine, and adenine, respectively, in DNA to make RNA. Like DNA polymerases, RNA polymerases catalyze polymerization of nucleotides only in the 5' to 3' direction antiparallel to its DNA template strand. Unlike DNA polymerases, RNA polymerases do not require a primer to initiate synthesis. B) Nuclear RNA polymerases of eukaryotic cells - There are 3 distinct classes of RNA polymerase in the nucleus of eukaryotic cells. All are large enzymes with multiple subunits. - Each class of RNA polymerase recognizes particular types of genes. 1. RNA polymerase I : This enzyme synthesizes the precursor of the large ribosomal RNAs in the nucleolus. [ mRNA and tRNA are synthesized in the nucleoplasm]. 2. RNA polymerase II : This enzyme synthesizes the precursors of messenger RNAs that are subsequently translated to produce proteins. Polymerase II also synthesizes certain small nuclear RNAs (snRNA) and is used by some viruses to produce viral RNA . 3. RNA polymerase III: This enzyme produces the small RNAs, including tRNAs, the small 5S ribosomal RNA. and some snRNAs . 4 C) Mitochondrial RNA polymerase: Mitochondria contain a single RNA polymerase that resembles bacterial RNA polymerase more closely than it does the eukaryotic enzyme . COMPLEMENTARY DNA (cDNA): The mRNA can be used as a template to make a complementary double stranded DNA (cDNA) molecule using the enzyme reverse transcriptase. Reverse transcriptase is an RNA-dependant DNA polymerase, i.e. it adds (T) in the newly synthesized strand for (A) in the template strand. Like all the other enzymes that synthesize nucleic acids, reverse transcriptase moves along the template in the 3'5' direction, synthesizing the cDNA product in the 5'3' direction but it lacks proofreading activity. The resulting cDNA is thus a double stranded molecule. The cDNA can be amplified by cloning or by the polymerase chain reaction (PCR). References: Lippincott’s Reviews of Biochemistry, 3rd edition by Champe PC, Harvey RA, Ferrier DR, Lippincott William & Wilkins London, 2005 Harper's Illustrated Biochemistry: 27th Edition by Murray RK, Granner DK, Mayes PA, Rodwell VW, McGraw-Hill companies New York, 2005 Text book of Biochemistry with Clinical Correlations 5th Edition, Devlin TM Ed,Wiley –Liss New York 2002 Fundamental of Clinical Chemistry, Tietz, N.W. Saunders, Philadelphia Essential Molecular Biology Review, Hall, P.W. , Blackwell Science, Oxford 5