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Module 1 Midterm Review.pdf

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Life Sciences
Joe Kim

Module 1 Midterm Review January-31-13 12:36 AM Telomere erosion & Aging theory What are Telomeres? - Telomeres are protein complexes that are at the end of DNA strands,which protect the DNA from the Ku proteins and prevent the loss of coding genes during DNA replication ○ Ku proteins repair Double Strand breaks which occur 10 times a day in our cells. Since the ends of chromosomes without telomeres resemble DNA damage, these Ku proteins tend to merge DNA strands together which can lead to mutations in the genome. - There are two types of telomeres: 1. Duplex Telomeric DNA: consists of 4 to 15 kilobases which caps the end of chromosomes 2. Single Stranded Telomeric DNA: consist of ~250 base pairs that have a 3' G-rich overhang - Telomeres shorten as we age, in males they start off with longer telomeres, that erode at a much higher rates than females. ○ This explains why females live 15% longer than males - To visualize telomeres we can use FISH. In this experiment we attach a complimentary DNA probe that is covalently bonded to fluorophore, denature the sample and wait for hybridization. After DNA repair we can see the telomeres under an fluorescent microscope Sheltrin - Telomeres are attached to the DNA strands via the sheltrin protein - Sheltrin protein consists of 6 protein complexes and promote the formation of T-loops ○ A T-loop is formed when the duplex telomeric DNA loops back and single stranded telomeric DNA invades the duplex telomeric DNA, forming a protective "cap" - T-loops can malfunction when there is mutation in the sheltrin protein or a malfunction during DNA replication, resulting in short telomeres - When the telomere is "critically" short it cannot form aT-loop, so p53 tumor suppressor is activated which signals cellular senescence (The cell no longer divides, and doesn't die) ○ Due to this the cells are no longer being renewed which results in increased risk of heart disease, liver failure, Alzheimer's and diabetes DNAreplication problem Telomeres shorten after each DNA replication because the lagging strand has a RNA primer that cannot be - replaced by the replication machinery due to a lack of a 3' end (DNA POL 3 can only work with 3' ends) ○ This is called "telomeric erosion" - This results in the said critically short telomeres Telomerase - How do Adult Stem Cells and Cancer Cells overcome the DNA replication problem, since they are able to proliferate indefinitely? - Using an enzyme called telomerase which contains an RNA template of the telomere, using this template this enzyme creates a DNA copy of the lose telomere which counters telomeric erosion - The telomerase lengthens the 3' over hang which is then filled by okazaki fragments, resulting in the telomere being synthesized during DNA replication Can telomerase activity result in longevity? - A study done in mice show that activating telomerase with the mTERT gene increases life expectancy and slows down telomeric erosion - TA-65 which was extracted from a herb (A. Membranaceous), shows signs of telomerase activation in cells that previously didn't have this expression Adult stem cells and Aging theory What are adult stem cells? - Adult stem cells are undifferentiated, limited cells that are present in the human body - When they divide they give rise to another adult stem cells (renewing the old one) and a needed somatic cell to replenish dying and aging cells - Adults stem cells have telomeric erosion, despite the fact that they have telomerase activated in them, but they age much slower than somatic cells age much slower than somatic cells - These cells lose their renewing ability by either one of two ways: 1. Inadequate telomerase expression to maintain telomere ends 2. DNA replication malfunction which results in cell senescence - When we start running out of adult stem cells to replace our dying and old cells, we start to age Cancer - Uncontrolled cell growth of abnormal cells in the body that metastasize to other tissues - 90% of cancer cells express telomerase, although all of them have figured out ways to maintain telomere length Role of telomeres in Cancer - Cancerous Adult Stem Cells: They already have telomerase activity so they are prone to becoming cancerous and DNA replication errors can lead to mutations resulting in cancer - Cancerous Somatic Cells: during replication malfunctions they acquire cancerous mutations such as activation of telomerase, oncogene activation and deactivation of p53 tumor suppressor ○ A somatic c
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