Lecture14 - Lecture#15 Tuesday-1 DNA Damage Direct result...

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Lecture #15 – Tuesday, 5/20/08 - 1 - DNA Damage - Direct result of aging DNA is continuously damaged DNA repair is critical to normal life (both in context of freedom from mutations leading to cancer as well as other diseases) o Due to exogenous or endogenous circumstances: Exogenous: carcinogens, oxidizing agents, UV light, mutagenic compounds/chemicals and other phenomenon Endogenous: related to amount of cell replication. (There is an error rate due to imperfection of process. If you go through a long process of assembly, there is going to be an error rate) DNA synthesis is no exception to this rule roughly 1 in 10 6 base pairs is an error Approximately 10 9 base pairs in genome, each time we recreate a cell we must resynthesize that genome. With an error rate of 1 in a million base pairs, we start getting a pretty decent mutational load early on in our lives. 1 in 10 10 base pairs is a mutant despite repair mechanisms, 1 mutation in every 10 cell divisions somewhere in the genome. (Large parts of genome are not expressed and because of wobble genes can stand certain types of mutations, so it won’t have that huge of an effect over a shorter term. But errors can add up over course of your lifetime.) - Proliferating cells are the most susceptible to DNA damage. They have an increased potential for spontaneous mutation. Because they are continuing to grow, also are more susceptible to effects of induced mutations (by carcinogens), because they are going through this growth process and can pass on these induced mutations onto daughter cells. The most sensitive compartment for DNA damage generally are proliferating cell populations in terms of DNA damage especially leading to cancer Synthetic DNA Damage types: - Error rate of 1 in 10 6 Aggressive ways of fixing DNA damage, but still typically after repair, often end up with 1 in 10 10 mutated base pairs - What can occur: - Changes that occur chemically - Misincorporation : insertion of wrong base - DNA “slippage” : associated with tandem repeats o Tandem repeats (of 2-4 repeated base pairs), because each unit looks like the one before it, often the case in DNA synthesis, replication fork can hop over these regions, replication for these regions can skip these repeats (for some reason). Alters overall gene expression/regulation. Cancer is essentially a disease of aging How aging and is related to tumorigenesis: 1. Hayflick Limit and telomere shortening. (talked about before) 2. Overall accumulation of mutational damage that occurs overtime despite correction repair processes.
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Lecture #15 – Tuesday, 5/20/08 - 2 - DNA Repair Mechanisms – how DNA repair can counteract these (see above on aging) Mismatch Repair - Particularly important for DNA slippage (hybridization of two strands of DNA after slippage results in a single strand loop) o Typically occur in tandem repeat sequences. -
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This note was uploaded on 07/21/2008 for the course BIMM 134 taught by Professor Johnson during the Spring '08 term at UCSD.

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Lecture14 - Lecture#15 Tuesday-1 DNA Damage Direct result...

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