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5. DNA Repair and Recombination.pdf

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Biology (Sci)
BIOL 200
Richard Roy

Naveen Sooknanan McGill Fall 2011 DNA Repair and Recombination: Over the course of evolution, errors in DNA replication can introduce permanent, transmissible changes into a daughter cell of organism. This is known as a mutation to DNA. This causes the encoding for different mRNA molecules after translation, and, eventually, different amino acids coded during translation.  Mutagens, on the other hand, are chemical compounds, ultraviolet radiation, or ionizing radiation (X-rays and atomic particles) which can increase the frequency of mutation. A carcinogen is an agent that causes cancer. All carcinogens are mutagens. Carcinogens can introduce the following changes into a normal cell:  Self-sufficiency in growth signals  Insensitivity to antigrowth signals  Evasion of apoptosis  Limitless replicative potential  Tissue invasion and metastasis  Sustained angiogenesis There are multiple methods of DNA repair through which the cell can prevent the occurrence of mutations. Each of the mechanisms can take place at different times after transcription in order to maximize effectiveness. Note that we will use a eukaryotic model to explain DNA repair.  E. coli DNA polymerase can introduce 1 error in every 10,000 nucleotides incorporated into new polynucleotide strands. An error incorporation rate like this would cause too many mutations to allow for our survival.  Due to the effectiveness of DNA repair mechanisms, the actual rate of error incorporation is in fact 1 in every 1,000,000 nucleotides after measures of correction. Some DNA polymerases have a proofreading activity which reads the newly synthesized strand in the 5’  3’ direction.  DNA polymerase δ, and not α, is able to read the new strand with an exonuclease activity o This is why Pol δ takes over for Pol α in DNA replication  When there is a mistake, Pol δ chews off the 3’ end of the new strand and repolymerizes it with the correct base pairing. Another mechanism, called base excision repair is able to fix errors after replication. It is used to fix errors caused by mutagens.  De-amination of cytosine into uracil can occur spontaneously in the cell, for example during cell metabolism o This is not good if it happens in DNA and must be repairs by base excision repair  Cytosine can also be methylated on carbon 5 via and enzyme called DNA methyltransferase o This is not necessarily a bad thing, in fact it is necessary for gene regulation, transposon silencing and chromatin remodelling (gene compacting) o Methylated cytosine can also be transformed into thymine by de-amination 1DNA glycosylase APEI endonuclease AP lyase (part of DNA Pol B) T T DNA Pol B LGL DNA ligase Repaired wild-type DNA Template strand MsH2 MSH6 3 endonuclease 3 by DNA polymerase and ligase DNA glycosylase APEI endonuclease AP lyase (part of DNA Pol B) T T DNA Pol B LGL DNA ligase Repaired wild-type DNA Template strand MsH2 MSH6 3 endonuclease 3 by DNA polymerase and ligaseNaveen Sooknanan McGill Fall 2011 Base excision repair undergoes a multitude of steps involving gap repair in order to repair one nucleotide in a polynucleotide strand.  DNA glycosylase hydrolyzes the bond between the mispaired base and the sugar phosphate backbone, leaving the backbone attached to the sequence and removing only the T in this example  Apurininc/Apyrimidinic Endonuclease 1 (APE1) cuts the sugar phosphate backbone at the 5’ end  AP lysase associates with DNA Polymerase β cuts the 3’ end of the sugar phosphate backbone (deoxyribose phosphate), removing it from the sequence  The new, correct nucleotide is brought in as a dNTP and is synthesized into the sequence by DNA polymerase β and the sugar phosphate backbone is ligated by DNA ligase (called gap repair). Mismatch excision repair is coupled with DNA replication; it happens shortly after replication takes place. This mechanism is used on newly synthesized strands where errors were incorporated and missed by proofreading. Once an error is introduced, a series of steps is taken out to carry out mismatch excision repair. This mechanism also involves gap repair.  Proteins MSH2 and MSH6 bind to the daughter strand and associate with the erroneous base o It’s not known how these complexes recognize which is the newly synthesized strand, but it must be able to in order for this mechanism to work  Endonuclease MLH1 and PMS2 bind to the complex and are then activated.  DNA helicase and DNA exonuclease then unwind and digest the area around the erroneous base.  Pol δ then synthesizes the removed area of the daughter strand,
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