SPEC COURSE INTRO TO NEUROSCIENCE
SPEC COURSE INTRO TO NEUROSCIENCE A&S 300
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This 6 page Class Notes was uploaded by Noah Wyman on Friday October 23, 2015. The Class Notes belongs to A&S 300 at University of Kentucky taught by Staff in Fall. Since its upload, it has received 10 views. For similar materials see /class/228228/a-s-300-university-of-kentucky in Arts and Sciences at University of Kentucky.
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Date Created: 10/23/15
Theories of aging telomeres and senescence AampS300002 Jim Lund Chromosome End Replication Problem Lagging Strand 31A 3 lt 5 Leading Strand RNA Primer 3 Terminal RNA Primer Cannot be Replicated DNA replication and telomere shortening 3 The l DNAreplscanonbogm chromosome End 3 MW Replication primertor loading strand synthssts rod Pmblem Laggingstmndsymhesisfblqu l l isnormal l r a dofRNAptimomsodi nicks DNA quot9 poymerases quotmwsKLoadingstrandisnoioon pieiolom It add bases 233 uggingszmnaisrlntshod quotl 5 gt 3 and require a lmtrepekedJMlomm l a badhgsmndprodmeslncraasingly l primer uuncaladmiomoro template 1 1227EA MV339 A l i39 l l 1amp 5 Consequences of the end replication problem 4 One strand replicates to the end a The other strand has a 8 12 bp gap atthe 5 end a Each chromosome in a cell that divides repeatedly will progressively shorten 4 Consequences Loss or inactivation of genes aging at Olovnikow 1973 What are telomeres Telomeres are lRepetitive DNA sequences at the ends of all human chromosomes bThey contain thousands of repeats of the six nucleotide sequence TTAGGG bln humans there are 46 chromosomes and thus 92 telomeres one at each end Chromosome Ends are specialized structures called Telomeres Blue DNA White Telomere protein TERT Telomeres 3 l39I39I39GGGG39ITGGGG I39I39GGGGTTGGGGWGGGGTI G IAACCCCAACCCCAACCCCAAC 51 Repeated G rich sequence on one strand in humans TTAGGGH Repeats can be several thousand basepairs long In humans telomeric repeats average 515 kilobases Telomere specific proteins eg TRF1 amp TRF2 bind to the repeat sequence and protect the ends Telomere functions Telomeres protect chromosome end from DNA repair pathways repair leads to chromosomal fusions Maintain length of chromosomes Telomeres associate with the nuclear membrane and maintain nuclear organization Telomerase t39 Telomerase is a ribonucleoprotein enzyme complex a cellular reverse transcriptase b TERT RNA directed DNA polymerase a TERC RNA template 1 It stabilizes telomere length by adding hexameric TTAGGG repeats onto the telomeric ends of the chromosomes thus compensating for the erosion of telomeres that occurs in its absence Telomerase is composed of both RNA and protein remainder of telomerase RNA telomerase protein 5 quotfingersquot re ion of telomerase RNA r used as template quot alm 7 act ve site oftelomerase rest of n w e ly 393 chromosome sy nthesized te Figure 5742 Molecular Biology of the Cell 4th Edition How Does Telomerase Work Telomerase works by adding back telomeric DNA to the ends of chromosomes thus compensating for the loss of telomeres that normally occurs as cells divide tMost normal cells do not have this enzyme and thus they lose telomeres with each division The telomere theory of aging i Potentially immortal cells germ cells cancer cells maintain telomerase activity I Can divide indefinitely Cells with a limited replicative lifespan 6 Should have no telomerase activity Iv Progressively shortening telomeres la Cell division serves as a mitotic clock for replicative senescence 46 Provides a mechanistic explanation for the Hayflick limit Hayflick limit cells are only capable ofa limited number of Cell proliferation potential greater in longlived species population doublings in gnaw Ha i0k Limit culture mouse about 3 years doublngs about 20 39 human about 100 doublings about 4060 Heres What is meant 39Galapagos tortoise about 150 doublings about 140 by the term doubling in Maximum Maximum Vim life span doubling 39 Species years number Term IS used to One serial passage or aifpagos tomlse 1Z3 13 describe replication doubling of cells Home 46 82 going on in culture Chicken 30 35 dishes Cal 28 92 Kangaroo 16 46 10 34 Mouse 4 28 population doublings Cell proliferation potential lower from older donors Cells from older donors have used upquot some of doublings Fetal Lung Adult Lung Dells divide unlll lhey cnmpletely cum medal 1nd nonlinth dlvudl Allera nlta numberolcell mulllyllnallws when platedlnlnslicullulim um w Number or Nu39nber of fit I 7 7 4 e ssm m v population population Age of 7 l quot l Egt Simln doublings Strain doubling donor cgt 6 w 51 wnooo 29 87 ms 35 xvi1001 18 so m3 lmsyem 112 33 300 1 23 Human iwwsl wma 55 xvimod 22 61 mm w my so WM 5 16 58 wrza 55 WHOM 14 53 Mouse MI W39lZl 59 M4007 20 26 25 50 75 mg as wrzs 41 Mullva papulzl mn dwb lh s cl eels in culture M27 41 was 43 W144 63 Average 20 nge 35 65 14 29 A 1 k 39 ml n i39 331 1 I l 7n A a a quot s39 a N s v 39 39 n 39wx 3 I V EV gt v L39 51M nquot 1 i 39fis39t quot Expdnentg l a lSenel39sgmg genescent Cellular senescence Once the telomere shrinks to a certain extent the cell stops dividing b4kb in human cells triggers end to cell division This leads to other changes called cellular senescence bCell morphology changes bGene expression changes Telomerase Activity In humans telomerase is active in germ cells in vitro immortalized cells the vast majority of cancer cells and possibly in some stem cells High telomerase activity exists in germ cells stem cells epidermal skin cells follicular hair cells and cancer cells lnactive in most cells somatic cells differentiated cells postmitotic cells Telomere also provide a means for quotcountingquot cell division telomeres shorten with each cycle Telomeres shorten from 1015 kb germ line to 35 kb after 5060 doublings average lengths of TRF5 M O Cellular senescence is triggered when NormaI cells acquire one or a few Somatic critically short telomeres Cells Telomerase Negative Cellular replicative Senescence Telomere Length humans 6 Number of Doublings Yeast replicative lifespan regulated by telomere length Telomerase mutants have a short lifespan When telomeres shorten to a critical point yeast cells stop dividing Overexpression oftelomerase Longertelomeres Increased replicative lifespan Subtelomeric gene expression is supressed Shortening of telomeres relieves the supression Telomeres in mice Lab strains of mice have very long telomeres 3040kbtelomeres 39 Ten knockout mice 0 Normal for four generations as their telomeres shorten Premature aging phenotypes present in the 5th generation Wern er s cellular phenotype reversed by telomerase expression cumulative population doublings a o 2395 50 75 100 125 150 195 200 225 250 2 5 days ln culture post infection Dermal fibroblasts transformed with TERT telomerase continue dividing Werner s cells typically stop dividing at 20 population doublings
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