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Biology, 9th ed,Sylvia Mader
Chapter 15 Gene Regulation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. regulator gene promoter operator structural genes DNA RNA polymerase 5¢ 3¢ mRNA inactive repressor enzymes a. Tryptophan absent. Enzymes needed to synthesize tryptophan are produced. RNA polymerase cannot bind to promoter. DNA active repressor tryptophan inactive repressor b. Tryptophan present. Presence of tryptophan prevents production of enzymes used to synthesize tryptophan.
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Outline Prokaryotic Regulation Eukaryotic Regulation Genetic Mutations
trp Operon lac Operon Eukaryotic Regulation Chromatin Structure Transcriptional Control Posttranscriptional Control Translational Control Posttranslational Control Genetic Mutations Cancer
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Prokaryotic Regulation
Bacteria do not require the same enzymes all the time Enzymes are produced as needed Francois Jacob and Jacques Monod (1961) proposed the operon model to explain regulation of gene expression in prokaryotes Operon is a group of structural and regulatory genes that function as a single unit
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Prokaryotic Regulation: The Operon Model
Operon consist of three components Promoter DNA sequence where RNA polymerase first attaches Short segment of DNA Operator DNA sequence where active repressor binds Structural Genes One to several genes coding for enzymes of a metabolic pathway Translated simultaneously as a block Long segment of DNA
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Repressible Operons: The trp Operon
The regulator codes for a repressor If tryptophan (an amino acid) is absent: Repressor is unable to attach to the operator (expression is normally “on”) RNA polymerase binds to the promoter Enzymes for synthesis of tryptophan are produced If tryptophan is present: Combines with repressor as corepressor Repressor becomes functional Blocks synthesis of enzymes and tryptophan
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transcription is prevented.
The trp Operon Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. promoter operator regulator gene structural genes When the repressor binds to the operator, transcription is prevented. active repressor
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The trp Operon regulator gene promoter operator structural genes DNA
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. regulator gene promoter operator structural genes DNA RNA polymerase 5¢ 3¢ mRNA inactive repressor enzymes a. Tryptophan absent. Enzymes needed to synthesize tryptophan are produced. RNA polymerase cannot bind to promoter. DNA active repressor tryptophan inactive repressor b. Tryptophan present. Presence of tryptophan prevents production of enzymes used to synthesize tryptophan.
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Inducible Operons: The lac Operon
The regulator codes for a repressor If lactose (a sugar that can be used for food) is absent: Repressor attaches to the operator Expression is normally “off” If lactose is present: It combines with repressor and renders it unable to bind to operator RNA polymerase binds to the promoter The three enzymes necessary for lactose catabolism are produced
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The lac Operon RNA polymerase cannot bind to promoter. regulator gene
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. RNA polymerase cannot bind to promoter. regulator gene promoter operator structural genes DNA active repressor active repressor a. Lactose absent. Enzymes needed to take up and use lactose are not produced. RNA polymerase can bind to promoter. DNA inactive repressor 5¢ 3¢ mRNA active repressor lactose enzymes b. Lactose present. Enzymes needed to take up and use lactose are produced only when lactose is present.
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Action of CAP CAP binding site promoter operator DNA
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. CAP binding site promoter operator DNA RNA polymerase binds fully with promoter. cAMP active CAP inactive CAP a. Lactose present, glucose absent (cAMP level high) CAP binding site promoter operator DNA RNA polymerase does not bind fully with promoter. inactive CAP b. Lactose present, glucose present (cAMP level low)
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Eukaryotic Regulation
A variety of mechanisms Five primary levels of control: Nuclear levels Chromatin Packing Transcriptional Control Posttranscriptional Control Cytoplasmic levels Translational Control Posttranslational Control
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Regulation of Gene Expression: Levels of Control in Eukaryotes
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. histones Chromatin structure Transcriptional control pre- mRNA 3¢ 5¢ intron exon Posttranscriptional control mRNA 5 ¢ 3¢ nuclear pore nuclear envelope Translational control polypeptide chain Posttranslational control plasma membrane functional protein
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Chromatin Structure Eukaryotic DNA associated with histone proteins
Together make up chromatin As seen in the interphase nucleus Nucleosomes: DNA wound around balls of eight molecules of histone proteins Looks like beads on a string Each bead a nucleosome The levels of chromatin packing determined by degree of nucleosome coiling
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Chromatin Structure Regulates Gene Expression
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. heterochromatin nucleolus euchromatin nucleosome inaccessible promoter 1 mm a. Darkly stained heterochromatin and lightly stained euchromatin chromatin remodeling complex H2B histone protein H2A H4 histone tail H3 accessible promoter DNA H1 DNA to be transcribed b. A nucleosome c. DNA unpacking a: Courtesy Stephen Wolfe
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Chromatin Packing Euchromatin Heterochromatin Barr Bodies
Loosely coiled DNA Transcriptionally active Heterochromatin Tightly packed DNA Transcriptionally inactive Barr Bodies Females have two X chromosomes, but only one is active Other is tightly packed along its entire length Inactive X chromosome is Barr body
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X-Inactivation in Mammalian Females
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Coats of tortoiseshell cats have patches of orange and black. active X chromosome allele for orange color inactive X cell division Barr bodies inactive X allele for black color active X chromosome Females have two X chromosomes. One X chromosome is inactivated in each cell. Which one is by chance. © Chanan Photo 2004
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Transcriptional Control
Transcription controlled by proteins called transcription factors Bind to enhancer DNA Regions of DNA where factors that regulate transcription can also bind Always present in cell, but most likely have to be activated before they will bind to DNA
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Eukaryotic Transcription Factors
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. DNA enhancer promoter gene transcription activator transcription factor complex mediator proteins RNA polymerase mRNA transcription
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Posttranscriptional Control
Posttranscriptional control operates on primary mRNA transcript Given a specific primary transcript: Excision of introns can vary Splicing of exons can vary Determines the type of mature transcript that leaves the nucleus May also control speed of mRNA transport from nucleus to cytoplasm Will affect the number of transcripts arriving at rough ER And therefore the amount of gene product realized per unit time
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Processing of mRNA Transcripts
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. intron exon intron exon 5¢ A B C D E 3¢ 5¢ A B C D E 3¢ cap pre-mRNA poly-A tail cap pre-mRNA poly-A tail RNA splicing RNA splicing intron intron C A B C D E A B D E mRNA mRNA protein product 1 protein product 2 a. b.
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Function of microRNAs pre-mRNA 5¢ 3¢ microRNA (miRNA)
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. pre-mRNA 5¢ 3¢ microRNA (miRNA) MicroRNA is cut from a pre-mRNA and binds with proteins to form RISC. 3¢ 5¢ RISC (RNA-induced silencing complex) proteins Complementary base pairing between RNAs allows RISC to bind to mRNA. mRNA 5¢ 3¢ RISC Translation is inhibited. or The mRNA is degraded.
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Translational Control
Translational Control - Determines degree to which mRNA is translated into a protein product Presence of 5′ cap Length of poly-A tail on 3′ end Posttranslational Control - Affects the activity of a protein product Activation Degradation rate
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Regulation Through Gene Mutation
Mutation is a permanent change in the sequence of bases in DNA. No effect on protein activity Protein is completely inactivated Germ-line mutations occur in sex cells Somatic mutations occur in body cells
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Causes of Mutations Spontaneous mutation Induced mutation:
DNA can undergo a chemical change Movement of transposons from one chromosomal location to another Replication Errors 1 in 1,000,000,000 replications DNA polymerase Proofreads new strands Generally corrects errors Induced mutation: Mutagens such as radiation, organic chemicals Many mutagens are also carcinogens (cancer causing) Environmental Mutagens Ultraviolet Radiation Tobacco Smoke
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The Ames Test For Mutagenicity
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Suspected chemical mutagen Control bacterial strain (requires histidine) bacterial strain (requires histidine) Plate onto petri plates that lack histidine. bacterial growth Incubate overnight Mutation occurred Mutation did not occur
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Causes of Mutations Ultraviolet (UV) radiation is easily absorbed by the pyrimidines in DNA. Cause neighboring thymine molecules next to one another to bond together Thymine dimers. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. C G kink T A T thymine dimer A C G
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Causes of Mutations Usually, these dimers are removed by DNA repair enzymes Deficient DNA repair enzymes leave the skin cells vulnerable to the mutagenic effects of ultraviolet light Accumulation of mutation High incidence of cancer
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Effect of Mutations on Protein Activity
Point Mutations Involve change in a single DNA nucleotide Changes one codon to a different codon Affects on protein vary: Nonfunctional Reduced functionality Unaffected Frameshift Mutations One or two nucleotides are either inserted or deleted from DNA Protein always rendered nonfunctional Normal : THE CAT ATE THE RAT After deletion: THE ATA TET HER AT After insertion: THE CCA TAT ETH ERA T
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XerodermaPigmentosome
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Ken Greer/Visuals Unlimited
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Point Mutations in Hemoglobin
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 3¢ 5¢ No mutation C A C G T G G A G T G A G G T C T C C T C Val His Leu Thr Pro Glu Glu His His (normal protein) C A C G T A G A G T G A G G T C T C C T C Val His Leu Thr Pro Glu Glu b. Normal red blood cell c. Sickled red blood cell Glu Val (abnormal protein) C A C G T G G A G T G A G G T C A C C T C Val His Leu Thr Pro Val Glu Glu Stop (incomplete protein) C A C G T G G A G T G A G G T A T C C T C Val His Leu Thr Pro Stop a. b, c: © Stan Flegler/Visuals Unlimited.
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Carcinogenesis Development of cancer involves a series of mutations
Proto-oncogenes – Stimulate cell cycle Tumor suppressor genes – inhibit cell cycle Mutation in oncogene and tumor suppressor gene: Stimulates cell cycle uncontrollably Leads to tumor formation
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Cell Signaling Pathway
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. inhibiting growth factor receptor plasma membrane signal transducers cytoplasm transcription factor protein that is unable to inhibit the cell cycle or promote apoptosis nucleus mutated tumor suppressor gene Cell signaling pathway that stimulates a mutated tumor suppressor gene
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Cell Signaling Pathway
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. stimulating growth factor receptor plasma membrane signal transducers cytoplasm transcription factor protein that overstimulates the cell cycle nucleus oncogene Cell signaling pathway that stimulates a proto-oncogene
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