Genetic regulation 06 08-13

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Genetic regulation 06 08-13

  1. 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 genome JACOB AND MONOD DR.RITTU CHANDEL MD BIOCHEMISTRY (2ND YEAR) DEPARTMENT OF BIOCHEMISTRY GRANT MEDICAL COLLEGE MUMBAI 06-08-13
  2. 2. – functional unit of DNA  Genome – total genetic information contained in cell  Gene expression – multistep process resulting in production of functional gene product  Gene regulation prokaryotes eukaryotes Level Transcription DNA level Transcription Post transcription Translation Post translation process fluctuates irreversible
  3. 3.  It is 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. 4.  Housekeeping or constitutive genes – encode products required for basic cellular function Continually expressed eg. Enzymes of TCA cycle Induction – increase the expression of particular product eg. Lac operon Repression – decreases the expression of particular product eg. Tryptophan operon
  5. 5.  Cistron – smallest unit of genetic expression one cistron – one subunit  Operon – linear array of coordinately controlled genes,turned on and off as a unit  Promoters – sequences that are important for transcription most common – rich in adenine and thymine ( TATA box ) other – GC box, CAA regulatory sequence – regulates transcription embedded in NCR of genome cis acting – when they influence expression of gene on same chromosome
  6. 6. sugar Lac operon Glucose Lactose Glucose and lactose Off ( negatively regulated) On ( positively regulated) Off ( negatively regulated)
  7. 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 symmetry Symmetry matching is a reccuring theme in DNA- protein interactions
  8. 8.  Recognize specific DNA sequences
  9. 9.  DNA binding 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. 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. 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. 12. Eg. Heme synthesis regulated by repression of ALA synthase
  13. 13. p p o l a trpe trpd trpb trpc trpa
  14. 14.  Genome larger  Nucleosome – complex of DNA and histones Not organized in operons  Transcription and translation are uncoupled  Many different cell types present in most eukaryotes
  15. 15.  1.Gene amplification Eg- in fruitfly in resistance to methotrexate
  16. 16.  DNA methylases are base and sequence specific  Prevents transcription  Heavily methylated – genes not expressed  5 azacytidine is inhibitor of methylases  Housekeeping genes rarely methylated  Requirment
  17. 17.  Chemical modification  Most important in preventing transcription  Plays a role in maintenance of inactive chromatin  Eg – barr body  globin genes in non – erythroid cells
  18. 18.  One gene 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. 19.  At 2 levels 1.chromosomal packaging Accessibility of transcription 2.individual gene regulation
  20. 20.  Requirement for gene expression  Chromatin structure is modulated through covalent modifications of histone tails  Histone acetyltransferase (HAT)
  21. 21.  Enhancer works 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. 22.  Transcription factors Transcription factors enhancer Transcription factors Transcription factors promoter Transcription factors
  23. 23.  Regulated by signals eg. Hormones  Properties 1.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. 24.  Similar to prokaryotic helix turn helix  Recognizes asymetric DNA sequences
  25. 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. 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. 27. BINDING MOTIF ORGANISM REGULATORY PROTEIN HELIX TURN HELIX E.coli Lac repressor ZINC FINGER Mammals Steroid receptor family LEUCINE ZIPPER Mammals CRE binding protein
  28. 28.  Alternartive splicing 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. 29.  May operate in nucleus or cytoplasm  Nucleus – hnRNA are produced which is not processed to mRNA  Cytoplasm vary considerably in their half lives
  30. 30.  Initiation factors 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. 31.  Modifications like folding, enzymatic clevage or bond formation  Proinsulin -------------------- insulin  Protein degradation
  32. 32.  SATYANARYAN  VASUDEVAN  PANKAJA NAIK  LIPPINCOTT  MARKS  HARPER  VOET  STRYER THANK YOU

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