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Lecture biology (6e) chapter 19 campbell, reece

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CHAPTER19THEORGANIZATION ANDCONTROLOFEUKARYOTIC GENOMES SectionA:EukaryoticChromatinStructure ChromatinstructureisbasedonsuccessivelevelsofDNApacking Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings Introduction ã Geneexpressionineukaryoteshastwomain differencesfromthesameprocessinprokaryotes ã First,thetypicalmulticellulareukaryoticgenomeis muchlargerthanthatofabacterium ã Second,cellspecializationlimitstheexpressionof manygenestospecificcells Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Theestimated35,000genesinthehumangenome includes an enormous amount of DNA that does  not program the synthesis of RNA or protein • This DNA is elaborately organized • Not only is the DNA associated with protein to form  chromatin, but the chromatin is organized into higher  organizational levels • Level of packing is one way that gene expression  isregulated ã Denselypackedareasareinactivated ã Looselypackedareasarebeingactivelytranscribed Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings 1.Chromatinstructureisbasedon successivelevelsofDNApacking ã Whilethesinglecircularchromosomeofbacteriais coiled and looped in a complex, but orderly manner,  eukaryotic chromatin is far more complex • Eukaryotic DNA is precisely combined with large  amounts of protein • During interphase of the cell cycle, chromatin fibers  are usually highly extended within the nucleus • During mitosis, the chromatin coils and condenses to  formshort,thickchromosomes Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Eukaryoticchromosomescontainanenormous amountofDNArelativetotheircondensedlength ã Eachhumanchromosomeaveragesabout2x108 nucleotidepairs ã Ifextended,eachDNAmoleculewouldbeabout6cm long,thousandsoftimeslongerthanthecelldiameter ã Thischromosomeand45otherhumanchromosomesfit intothenucleus ã Thisoccursthroughanelaborate,multilevelsystemof DNApacking Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Histoneproteinsareresponsibleforthefirstlevel of DNA packaging • Their positively charged amino acids bind tightly to  negatively charged DNA • The five types of histones are very similar from one  eukaryote to another and are even present in bacteria • Unfolded chromatin has the appearance of beads  on a string, a nucleosome, in which DNA winds  aroundacoreofhistoneproteins. Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Thebeadedstringseemstoremainessentially intactthroughoutthecellcycle ã HistonesleavetheDNAonlytransientlyduring DNAreplication ã TheystaywiththeDNAduringtranscription • By changing shape and position, nucleosomes allow  RNA­synthesizing polymerases to move along the  DNA.  Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings • As chromosomes enter mitosis the beaded string  undergoes higher­order packing • The beaded string coils to form the 30­nm  chromatinfiber ã Thisfiberformsloopeddomainsattachedtoa scaffoldofnonhistoneproteins. Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Inamitotic chromosome, theloopeddomains coilandfoldto produce the  characteristic  metaphase  chromosome • These packing steps are highly specific  and precise with  particular genes located in the same  places. Fig.19.1 Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Interphasechromatinisgenerallymuchless condensedthanthechromatinofmitosis ã Whilethe30ưnmfibersandloopeddomainsremain,the discretescaffoldisnotpresent ã Theloopeddomainsappeartobeattachedtothe nuclearlaminaandperhapsthenuclearmatrix ã Thechromatinofeachchromosomeoccupiesa restrictedareawithintheinterphasenucleus ã Interphasechromosomeshaveareasthatremain highlycondensed,heterochromatin,andless compactedareas,euchromatin. Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings • The products of proto­oncogenes, proteins that  stimulate normal cell growth and division, have  essential functions in normal cells • An oncogene arises from a genetic change that  leads to an increase in the proto­oncogene’s  protein or the activity of each protein molecule • These genetic changes include movements of DNA  withinthegenome,amplificationofprotoư oncogenes,andpointmutationsinthegene Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Malignantcellsfrequentlyhavechromosomesthat havebeenbrokenandrejoinedincorrectly ã Thismaytranslocateafragmenttoalocationnearan activepromotororothercontrolelement ã Amplificationincreasesthenumberofgenecopies ã Apointmutationmayleadtotranslationofa proteinthatismoreactiveorlongerưlived Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings Fig.19.13 Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Mutationstogeneswhosenormalproductsinhibit celldivision,tumorưsuppressorgenes,also contribute to cancer • Any decrease in the normal activity of a tumor­ suppressor protein may contribute to cancer • Some tumor­suppressor proteins normally repair  damaged DNA, preventing the accumulation of cancer­ causing mutations • Others control the adhesion of cells to each other or to  anextracellularmatrix,crucialfornormaltissues ã Stillothersarecomponentsofcellưsignalingpathways thatinhibitthecellcycle Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings 2.Oncogeneproteinsandfaultytumorư suppressorproteinsinterferewithnormal signalingpathways ã Mutationsintheproductsoftwokeygenes,theras protoưoncogene,andthep53tumorsuppressorgene occurin30%and50%ofhumancancers respectively ã BoththeRasproteinandthep53proteinare componentsofsignalưtransductionpathwaysthat conveyexternalsignalstotheDNAinthecells nucleus Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Ras, the product of the ras gene, is a G protein that  relays a growth signal from a growth factor  receptor to a cascade of protein kinases • At the end of the pathway is the synthesis of a protein  that stimulates the cell cycle • Many ras oncogenes have a point mutation that leads to  a hyperactive version of the Ras protein that can issue  signals on its own, resulting in excessive cell division • The tumor­suppressor protein encoded by the  normal p53 gene is a transcription factor that  promotes synthesis of growth­inhibiting proteins • A mutation that knocks out the p53 gene can lead to  excessive cell growth and cancer Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings • Mutations that result in stimulation of growth­stimulating pathways or deficiencies ingrowthư inhibiting pathways leadto increased celldivision Fig.19.14 Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã The p53 gene, named for its 53,000­dalton protein  product, is often called the “guardian angel of the  genome” • Damage to the cell’s DNA acts as a signal that  leads to expression of the p53 gene • The p53 protein is a transcription factor for several  genes • Itcanactivatethep21gene,whichhaltsthecellcycle ã ItcanturnongenesinvolvedinDNArepair ã WhenDNAdamageisirreparable,thep53proteincan activatesuicidegeneswhoseproteinproductscause celldeathbyapoptosis Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings 3.Multiplemutationsunderliethe developmentofcancer • More than one somatic mutation is generally needed  to produce the changes characteristic of a full­ fledged cancer cell • If cancer results from an accumulation of mutations,  and if mutations occur throughout life, then the  longer we live, the more likely we are to develop  cancer Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings • Colorectal cancer, with 135,000 new cases in the  U.S. each year, illustrates a multi­step cancer path.  • The first sign is often a polyp, a small benign  growth in the colon lining with fast dividing cells • Through gradual accumulation of mutations that  activate oncogenes and knock out tumor­ suppressor genes, the polyp can develop into a  malignanttumor. Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings Fig.19.15 Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã AboutahalfdozenDNAchangesmustoccurfora celltobecomefullycancerous ã Theseusuallyincludetheappearanceofatleast oneactiveoncogeneandthemutationorlossof several tumor­suppressor genes • Since mutant tumor­suppressor alleles are usually  recessive, mutations must knock out both alleles.  • Most oncogenes behave as dominant alleles • In many malignant tumors, the gene for telomerase  is activated, removing a natural limit on the  number of times the cell can divide Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Viruses,especiallyretroviruses,playaroleis about15%ofhumancancercasesworldwide ã Theseincludesometypesofleukemia,livercancer,and cancerofthecervix ã Virusespromotecancerdevelopmentby integratingtheirDNAintothatofinfectedcells • By this process, a retrovirus may donate an  oncogene to the cell • Alternatively, insertion of viral DNA may disrupt a  tumor­suppressor gene or convert a proto­ oncogene to an oncogene Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings • The fact that multiple genetic changes are required  toproduceacancercellhelpsexplainthe predispositionstocancerthatruninsomefamilies. ã Anindividualinheritinganoncogeneoramutantallele ofatumorưsuppressorgenewillbeonestepcloserto accumulatingthenecessarymutationsforcancerto develop Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Geneticistsaredevotingmuchefforttofinding inherited cancer alleles so that predisposition to  certain cancers can be detected early in life • About 15% of colorectal cancers involve inherited  mutations, especially to DNA repair genes or to the  tumor­suppressor gene APC • Normal functions of the APC gene include regulation  of cell migration and adhesion • Between5ư10%ofbreastcancercases,the2ndmost commonU.S.cancer,showaninheritedpredisposition ã Mutationstooneoftwotumorưsuppressorgenes, BRCA1andBRCA2,increasestheriskofbreastand ovariancancer Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ... compacted areas, euchromatin.  Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings CHAPTER? ?19? ? THE ORGANIZATION  AND CONTROL OF EUKARYOTIC  GENOMES Section B: Genome Organization at the DNA Level... millions of subpopulations of B lymphocytes Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings CHAPTER? ?19? ? THE ORGANIZATION  AND CONTROL OF EUKARYOTIC  GENOMES Section C: The Control of Gene Expression... There are three types  of satellite DNA,  differentiated by the  total length of DNA at each site Table? ?19. 1 top Copyrightâ2002PearsonEducation,Inc.,publishingasBenjaminCummings ã Anumberofgeneticdisordersarecausedby

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