端粒和端粒酶telomeres and telomerase

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Chromosome Parts,-Origins,Centromeres,&Telomeres,Every chromosome has to contains one centromere,two telomeres,and multiple origins of replication,Every chromosome,has multiple origins,of replication.These,origins fire only once,per cell cycle,Euchromatic and,Heterochromatic regions,replicate at different times,during S phase.,Euchromatin-early,Heterochromatin-late,Every chromosome has to contains one centromere,two telomeres,and multiple origins of replication,Centromeres are required for the segregation of,chromosomes during mitosis,Mitotic chromosome,condensation is driven,by ATPases called,Condensins,Organization of a Centromere,Centromeric Heterochromatin contains special nucleosomes,=,CENP-A,Every chromosome has to contains one centromere,two telomeres,and multiple origins of replication,Chromosome Ends are specialized structures called Telomeres,Blue=chromosomesWhite=Telomere protein,Repeated G rich sequence on one strand,in humans:(TTAGGG),n,Repeats can be several thousand basepairs long.In humans,telomeric repeats average 5-15 kilobases,Telomere specific proteins,eg.TRF1&TRF2 bind to,the repeat sequence and protect the ends,Without these proteins,telomeres are acted upon by DNA,repair pathways leading to chromosomal fusions,Telomeres,The End,Replication,Problem,The end replication problem leads to loss of information,from opposite strands at both ends,5,3,5,3,5,3,5,3,5,3,5,3,+,5,3,5,3,5,3,5,3,+,5,3,5,3,5,3,5,3,5,3,5,3,+,+,5,3,5,3,+,Without some form of correction the end replication problem,leads to the loss of 50-100 nucleotides from the newly,synthesized lagging strand at each chromosome end in each,round of duplication,In mammalian(and many other)cells,the solution to this,problem is that chromosome ends have a special duplication,machinery,=Telomerase,Different types of Nucleotide Polymerases,DNA,polymerase,Uses a DNA template to synthesize a DNA strand,2),RNA polymerase,Uses a DNA template to synthesize an RNA strand,(=transcription),3)Reverse transcriptase,Uses an RNA template to synthesize a DNA strand,Found in many viruses,Telomerase is a specialized reverse transcriptase,Telomerase is composed of both RNA and protein,and Primase,Telomeres are packaged into a unique structure-a T-loop,Green=,Telomere-specific proteins,T-loop seen,in the electron,microscope,In most somatic tissues,telomerase is expressed at very,low levels or not at all-as cells divide,telomeres shorten,Telomerase and Senescence,Short telomeres may be a signal for cells to senesce(stop dividing),Evidence that shortening of telomeres may be a signal,to stop cellular division,:,-Primary cells taken from the body and grown in vitro,will divide a few times and then stop.,If the gene encoding the catalytic subunit of Telomerase,is expressed in these primary cells,they grow for many,more divisions.,-Proliferating cells in the body(stem cells/germ cells),express telomerase,-Cancer cells express telomerase,Telomerase and Cancer,The presence of telomerase in cancer cells allows them to,maintain telomere length while they proliferate,Could turning off telomerase in cancer cells cause them to,senesce and thereby stop progression of the disease?,Maybe,Studies in an important model system,Telomerase deficient mice,indicate that it will probably depend on the type of tumor.,Telomerase and Cancer,Sensed as DNA,damage by the,p53 checkpoint,Stops Cell Division,Short telomeres cause growth arrest via a checkpoint,If the cells of a particular tumor still have p53,this works,Sensed as DNA,damage by the,p53 checkpoint,Cell division continues,without telomeres,leading to chromosomal,rearrangements,Buttumor cells often lack p53,This genomic instability can,promote tumorigenesis,Because there is very little telomerase in somatic tissues,older people have shorter telomeres,-particularly in actively regenerating tissues such as,skin or intestinal ephithelia,This has generated a lot of interest in the possibility that,telomere length could be tied to aging,Telomerase and Aging,Aging(mean life span)is influenced by environmental,factors,E.g.,Caloric Restriction,Rodents kept on a very restricted calorie diet live,on,average about 35%longer than control animals maintained,on full diet.,“Restricted diet”is roughly the equivalent of a human living on,600 calories/day,In“lower organisms”such as roundworms or yeast,caloric,restriction also increases lifespan,Aging(mean life span)is also influenced by genetic,traits,Specific mutations have been identified in model organisms,such as worms,flies,and yeast that lead to extension of lifespan,Analysis of such mutants holds out the possibility of understanding,the molecular mechanisms of aging,Sir2 was originally identified in yeast.It encodes a,component of heterochromatin and localizes to telomeres,It is an enzyme required for the formation of heterochromatin,in yeast,One such mutant that affects