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Genetic regulation 06 08-13

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  • 1.The fundamental of chemical physiology and of embryology is to understand why tissue cells do not all express, all the time, all the potentialities inherit in their genomeJACOB AND MONOD DR.RITTU CHANDEL MD BIOCHEMISTRY (2ND YEAR) DEPARTMENT OF BIOCHEMISTRY GRANT MEDICAL COLLEGE MUMBAI 06-08-13

2. functional unit of DNA Genome total genetic information contained in cell Gene expression multistep process resulting in production of functional gene product GeneregulationprokaryoteseukaryotesLevelTranscriptionDNA level Transcription Post transcription Translation Post translationprocessfluctuatesirreversible 3. Itis absolutely essential for growth, development, differentiation and very existence of an organism It answers to if, how much and when particular gene product is made Rapidly adjusts ( half life of mRNA is low) eg. Insulin synthesized by pancreatic cell although nuclei of all cells contain insulin gene 4. Housekeeping or constitutive genes encode products required for basic cellular function Continually expressed eg. Enzymes of TCA cycleInduction increase the expression of particular product eg. Lac operon Repression decreases the expression of particular product eg. Tryptophan operon 5. Cistron smallest unit of genetic expression one cistron one subunitOperon linear array of coordinately controlled genes,turned on and off as a unitPromoters sequences that are important for transcription most common rich in adenine and thymine ( TATA box ) other GC box, CAAregulatory sequence regulates transcription embedded in NCR of genome cis acting when they influence expression of gene on same chromosome 6. sugarLac operonGlucose Lactose Glucose and lactoseOff ( negatively regulated) On ( positively regulated) Off ( negatively regulated) 7. Nucleotide sequences of regulatory site shows a nearly perfect inverted repeat, indicating that DNA in this region has an approximately two fold axis of symmetrySymmetry matching is a reccuring theme in DNA- protein interactions 8. Recognizespecific DNA sequences 9. DNAbinding unit comes from protein lac repressor Alpha helix from each monomer of protein is inserted into the major groove of DNA, where amino acid side chains make specific contacts with exposed edges of base pairs 10. These interactions allow the lac repressor to bind more tightly to the specific site than to the wide range of other sites present in E.coli genome 11. common to many prokaryotic DNA BINDING PROTEINS Pair of alpha helices separated by tight turn 2nd of these two helices is recognition helix Residues of 1st helix participate in contacts with DNA backbone exception- methionine repressor Is 12. Eg. Heme synthesis regulated by repression of ALA synthase 13. p polatrpetrpdtrpb trpctrpa 14. Genomelarger Nucleosome complex of DNA and histones Not organized in operons Transcription and translation are uncoupled Many different cell types present in most eukaryotes 15. 1.GeneamplificationEg- in fruitfly in resistance to methotrexate 16. DNAmethylases are base and sequence specific Prevents transcription Heavily methylated genes not expressed 5 azacytidine is inhibitor of methylases Housekeeping genes rarely methylated Requirment 17. Chemicalmodification Most important in preventing transcription Plays a role in maintenance of inactive chromatin Eg barr body globin genes in non erythroid cells 18. Onegene is switched off while a closely related gene takes up its function Hb synthesis epsilon zeta (embryo) alpha gamma (6th month)alpha beta (after birth) Immunoglobin synthesis IgM to IgG 19. At2 levels 1.chromosomal packaging Accessibility of transcription 2.individual gene regulation 20. Requirementfor gene expression Chromatin structure is modulated through covalent modifications of histone tails Histone acetyltransferase (HAT) 21. Enhancerworks by facilitating the binding of basic transcriptional complex to promoter works when oriented in any direction exert positive influence on transcription even when separated by 1000s of bp from promoters 22. TranscriptionfactorsTranscription factorsenhancerTranscription factorsTranscription factorspromoterTranscription factors 23. Regulatedby signals eg. Hormones Properties1.redundant 2.acts synergestically Have one functional domain for DNA binding and one for transcription activation Can be classified according to structure of their DNA binding domains 24. Similarto prokaryotic helix turn helix Recognizes asymetric DNA sequences 25. 2 cysteine and two histidine residues seperated by 12 amino acids Cysteine residues are seperated by 2 amino acids Histidine residues seperated by 3 amino acids Loop that interacts with the major groove of DNA 26. 2 polypeptides join to form Y shaped dimer whose arms can interact with major groove of DNA Stem leucine zipper Pair of long alpha helices 1st part basic, makes contacts responsible for DNA recognition site 2nd part - forms coiled coil structure with its partner 27. BINDING MOTIFORGANISMREGULATORY PROTEINHELIX TURN HELIXE.coliLac repressorZINC FINGERMammalsSteroid receptor familyLEUCINE ZIPPERMammalsCRE binding protein 28. Alternartivesplicing varied products are produced average human genome is thought to code for 3 different proteins depending on exons retained in splicing calcitonin gene 1.In thyroid gland 2.In neurons 29. Mayoperate in nucleus or cytoplasm Nucleus hnRNA are produced which is not processed to mRNA Cytoplasm vary considerably in their half lives 30. Initiationfactors are involved Action of initiation factor inhibited when phosphorylated by protein kinase Eg. Reticulocytes no nuclei, must regulate synthesis of globin at translational level When heme is high, globin is produced heme prevents phosphorylation of initiation factors 31. Modificationslike folding, enzymatic clevage or bond formation Proinsulin -------------------- insulin Proteindegradation 32. SATYANARYAN VASUDEVAN PANKAJANAIK LIPPINCOTT MARKS HARPER VOET STRYERTHANK YOU