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Post-Transcriptional Modification by / Hanaa Shawky Ragheb Supervised by Prof.Dr / Rasha El Tahan Course / Molecular Biology

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Post-Transcriptional Modification by / Hanaa Shawky Ragheb Supervised by Prof.Dr / Rasha El Tahan Course / Molecular Biology Post-transcriptional modification By / Hanaa Shawky Ragheb Supervised by prof.dr / Rasha El Tahan Course / Molecular Biology Molecular biology: is a branch of science concerning biological activity at the molecular level. The field of molecular biology overlaps with biology and chemistry and in particular, genetics and biochemistry. A key area of molecular biology concerns understanding how various cellular systems interact in terms of the way DNA, RNA and protein synthesis function. Molecular biology looks at the molecular mechanisms behind processes such as replication, transcription, translation and cell function. One way to describe the basis of molecular biology is to say it concerns understanding how genes are transcribed into RNA and how RNA is then translated into protein. However, this simplified picture is currently be reconsidered and revised due to new discoveries concerning the roles of RNA. Central Dogma (Gene Expression): The central dogma of molecular biology explains that the information flow for genes is from the DNA genetic code to an intermediate RNA copy and then to the proteins synthesized from the code. The key ideas underlying the dogma were first proposed by British molecular biologist Francis Crick in 1958. Replication : DNA replication The formation of new and, hopefully, identical copies of complete genomes. DNA replication occurs every time a cell divides to form two daughter cells. Under the influence of enzymes, DNA unwinds and the two strands separate over short lengths to form numerous replication forks, each of which is called a replicon. The separated strands are temporarily sealed with protein to prevent re-attachment. A short RNA sequence called a primer is formed for each strand at the fork. These primers provide a free 3'- OH end on which the new complementary sequence can be formed along the strand. The LEADING STRAND is synthesized continuously in the 5’ to 3’ direction, working towards the fork direction with removal of the RNA primers as the parental duplex is unwound. The LAGGING STRAND is synthesized discontinuously in the opposite direction as short fragments called Okazaki fragments. Lagging strand synthesis requires extension of the primer, then removal of the primers and gap filling. At least 20 different enzymes and factors, including DNA helicases, DNA polymerases, RNA primases, DNA TOPOISOMERASES and DNA ligases are involved in the complex process of DNA replication. DNA Transcription Takes Place in the Nucleus: The DNA helix that encodes the organism’s genetic information is located in the nucleus of eukaryotic cells. Prokaryotic cells are cells that don't have a nucleus, so DNA transcription, translation and protein synthesis all take place in the cell's cytoplasm via a similar (but simpler) transcription/translation process. In eukaryotic cells, DNA molecules can’t leave the nucleus, so cells have to copy the genetic code to synthesize proteins in the cell outside the nucleus. The transcription copying process is initiated by an enzyme called RNA polymerase. Post-transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, functional RNA molecule that can then leave the nucleus and perform any of a variety of different functions in the cell. [1] There are many types of post-transcriptional modifications achieved through a diverse class of molecular mechanisms Perhaps the most notable example is the conversion of precursor messenger RNA transcripts into mature messenger RNA that is subsequently capable of being translated into protein. This process includes three major steps that significantly modify the chemical structure of the RNA molecule: the addition of a 5' cap, the addition of a 3' polyadenylated tail, and RNA splicing. Such processing is vital for the correct translation of eukaryotic genomes because the initial precursor mRNA produced by transcription often contains both exons (coding sequences) and introns (non-coding sequences); splicing removes the introns and links the exons directly, while the cap and tail facilitate the transport of the mRNA to a ribosome and protect it from molecular degradation. [2] Post-transcriptional modifications may also occur during the processing of other transcripts which ultimately become transfer RNA, ribosomal RNA, or any of the other types of RNA used by the cell. The structure of a eukaryotic protein-coding gene. Regulatory sequence controls when and where expression occurs for the protein coding region (red). Promoter and enhancer regions (yellow) regulate the transcription of the gene into a pre-mRNA which is modified to remove introns (light grey) and add a 5' cap and poly-A tail (dark grey). The mRNA 5' and 3' untranslated regions (blue) regulate translation into the final protein product.[3] The structure of a prokaryotic operon of protein-coding genes. Regulatory sequence controls when expression occurs for the multiple protein coding regions (red). Promoter, operator and enhancer regions (yellow) regulate the transcription of the gene into an mRNA. The mRNA untranslated regions (blue) regulate translation into the final protein products.[3] mRNA processing: The pre-mRNA molecule undergoes three main modifications. These modifications are 5' capping, 3' polyadenylation, and RNA splicing, which occur in the cell nucleus before the RNA is translated.[4] 5' processing: Capping Capping of the pre-mRNA involves the addition of 7-methylguanosine (m7G) to the 5' end. To achieve this, the terminal 5' phosphate requires removal, which is done with the aid of a phosphatase enzyme. The enzyme guanosyl transferase then catalyses the reaction, which produces the diphosphate 5' end. The diphosphate 5' end then attacks the alpha phosphorus atom of a GTP molecule in order to add the guanine residue in a 5'5' triphosphate link. The enzyme (guanine-N7-)-methyltransferase ("cap MTase") transfers a methyl group from S-adenosyl methionine to the guanine ring.[5] This type of cap, with just the (m7G) in position is called a cap 0 structure. The ribose of the adjacent nucleotide may also be methylated to give a cap 1. Methylation of nucleotides downstream of the RNA molecule produce cap 2, cap 3 structures and so on. In these cases the methyl groups are added to the 2' OH groups of the ribose sugar. The cap protects the 5' end of the primary RNA transcript from attack by ribonucleases that have specificity to the 3'5' phosphodiester bonds.[6] 3' processing: Cleavage and polyadenylation The pre-mRNA processing at the 3' end of the RNA molecule involves cleavage of its 3' end and then the addition of about 250 adenine residues to form a poly(A) tail. The cleavage and adenylation reactions occur primarily if a polyadenylation signal sequence (5'- AAUAAA-3') is located near the 3' end of the pre-mRNA molecule, which is followed by another sequence, which is usually (5'-CA-3') and is the site of cleavage. A GU-rich sequence is also usually present further downstream on the pre-mRNA molecule. More recently, it has been demonstrated that alternate signal sequences such as UGUA upstream off the cleavage site can also direct cleavage and polyadenylation in the absence of the AAUAAA signal. It is important to understand that these two signals are not mutually independent and often coexist. After the synthesis of the sequence elements, several multi-subunit proteins are transferred to the RNA molecule. The transfer of these sequence specific binding proteins cleavage and polyadenylation specificity factor (CPSF), Cleavage Factor I (CF I) and cleavage stimulation factor (CStF) occurs from RNA Polymerase II. The three factors bind to the sequence elements. The AAUAAA signal is directly bound by CPSF. For UGUA dependent processing sites, binding of the multi protein complex is done by Cleavage Factor I (CF I). The resultant protein complex formed contains additional cleavage factors and the enzyme Polyadenylate Polymerase (PAP). This complex cleaves the RNA between the polyadenylation sequence and the GU-rich sequence at the cleavage site marked by the (5'- CA-3') sequences. Poly(A) polymerase then adds about 200 adenine units to the new 3' end of the RNA molecule using ATP as a precursor. As the poly(A) tail is synthesized, it binds multiple copies of poly(A)-binding protein, which protects the 3'end from ribonuclease digestion by enzymes including the CCR4-Not complex.[6] Introns Splicing: RNA splicing is the process by which introns, regions of RNA that do not code for proteins, are removed from the pre-mRNA and the remaining exons connected to re-form a single continuous molecule. Exons are sections of mRNA which become "expressed" or translated into a protein. They are the coding portions of a mRNA molecule.[7] Although most RNA splicing occurs after the complete synthesis and end-capping of the pre-mRNA, transcripts with many exons can be spliced co-transcriptionally.[8] The splicing reaction is catalyzed by a large protein complex called the spliceosome assembled from proteins and small nuclear RNA molecules that recognize splice sites in the pre-mRNA sequence. Many pre-mRNAs, including those encoding antibodies, can be spliced in multiple ways to produce different mature mRNAs that encode different protein sequences. This process is known as alternative splicing, and allows production of a large variety of proteins from a limited amount of DNA. Histone mRNA processing: Histones H2A, H2B, H3 and H4 form the core of a nucleosome and thus are called core histones. Processing of core histones is done differently because typical histone mRNA lacks several features of other eukaryotic mRNAs, such as poly(A) tail and introns. Thus, such mRNAs do not undergo splicing and their 3' processing is done independent of most cleavage and polyadenylation factors. Core histone mRNAs have a special stem-loop structure at 3-prime end that is recognized by a stem–loop binding protein and a downstream sequence, called histone downstream element (HDE) that recruits U7 snRNA.
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