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This 5 page Class Notes was uploaded by Armaghan Fazal on Sunday February 1, 2015. The Class Notes belongs to bmb509 at University of Miami taught by Dr. Rik Myers in Fall. Since its upload, it has received 133 views. For similar materials see molecular biology of the gene in Biochemistry at University of Miami.
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Date Created: 02/01/15
11415 DNA Replication and principles 33 billion base pairs In humans there are at least 17 DNA polymerases Arthur s DNA polymerase 1 is the most abundant polymerase Conditional lethal mutations are mutations that are in essential genes that under a nonpermissive media that doesn t allow for replication conditions lead to lack of growth temp sensitive DNA pol nds DNA by Brownian motion and via diffusion They randomly collide with DNA or with proteins bound to DNA which leads to a stable interaction if af nity exists Replisome is a multiple protein complex that DNA pol is within that replicate DNA Origin is a sequence where replication begins by being distinct enough due to asymmetry Delta Delta G is high there is a high af nity ORC origin recognition complex bind to origins to attract a helicase and primase Helicase is a ring that has a little opening that encompasses the single stranded DNA Processive enzymes enzymes that can bind consecutive reactions without releasing its substrate DNA pol keeps binding nucleotides without falling off the DNA strand ORC DNA A opens us the DNA NOT the Helicases Rich in AT sequences Helicase is loaded in Helicase Loader via ATP This causes the recruitment of Primase via diffusion Primase RNA primase Places a 3 prime hydroxyl group adjacent to One does not need RNA for DNA synthesis RNA primer doesn t have to be RNA it could be DNA PCR primers are always DNA DNA synthesis requires a RNA primer but RNA synthesis does not need a primer We require a RNA primer because RNA synthesis is used as a primer to DNA look this us IMPT Primer Template Complez what is bound by DNA Pol Primer template plus DNA pol is now the active site It is not enough to get reactants close enough to each other but the reactants have to be oriented in the correct orientation otherwise the reaction rate goes down a millionfold It is not simply the AT but the right orientation The orientation is random so NTP s are hitting the DNA pol and if the orientation is not right they bounce off until we get on that is the right base pair and has the right orientation There is has to be a balance between delity and speed Processivity is the number of catalytic turnovers per binding unit In DNA synthesis is the number of nucleotides added per binding unit Promoter sequences there are sequences that are faster and better binding than other If we made a promoter sequences with all the good parts than DNA Pol had trouble leaving it and moving to the next step Sliding clamp can be open or shut clamp loaderunloader is the protein that opens and shuts it Since rings are not really touching the DNA strand this allows for nearly frictionless movement and we can move at the rate determining step of helicase Replisomes complexes of many proteins Continuous DNA synthesis has only one primer at the beginning but the lagging strand has money 12115 Fidelity 1 disincorporation for every 100000 for polymerase Proof reading nucleus is 3 to prime because that is the free end of the nascent strand impt it is part of the polymerase but it moves in the opposite direction of the polymerase so they have to give and take The rate of incorporation is higher than the rate of removal and the rate of deletion is higher than MMR mismatch repair repairs once polymerase is moved on and has failed to catch the mistake Some of these are associated with the replisome and some are free oating on the DNA Lagging strand has more DNA ends and has the higher rate of mismatch corrections The end of leading strand is wherever the 3 hydroxyl group OH IS Simple Template Abasic site is a nucleotide with the adenine or guanine etc is missing so it is only ribose sugar and mono phosphate DNA polymerase will stop if it encounters anything other than an ATGC Will stop if abasic site present Dissociation rate of DNA po is 100 at an abasic site Asymmetry of abasic site makes it highly identi able and hence it is removed prior to DNA pol gets to it If DNA pol get to it before it is removed replication stops because does not have a template to read off and x so we have a double strand break gtEND OF LIFE Abasic site or a site like it such as TT dimers made due to UV light get xed by a process the cuts it out 2 breaks and then use the other DNA strand as template to make new strand bit Replication fork collapse is a double stranded break which happens when there is an excision of strand but before it can be repaired the DNA pol get to it which leads to a double stranded break 0 Nucleotide excision repair is TEMPLATE DEPENDENT This is why we have a double helix because there is a back up CODY o Mismatch repair basic repair nucleotide repair are all EXCISION repair 0 Basic repair is preferred to gtnuceotide which is preferred to gtmismatch HOG enzymes are suicide enzymes because they are consumedthis is template INDEPENDENT 17 pol in human and most are repair pol Last polymerase adds random nucleotides if nucleotides are missingow kinetic activity compare 0 Repair pol have higher misincorporation rate than DNA pol and hence have a higher speed IDEA is when things go bad it is better to have local mutations rather than stoping transcription all together 0 repair pols llower delity but higher kinetic rate 0 when replisome encounters an abasic site pushes back creating a chicken foot which allows it to move passed the abasic site while using the other strand as the template and moves on This is preferred because it has higher delity than repair pols Look at structures and videos to understand 12615 0 alfatoxin carcinogen in peanut butter 0 Increases the tumor growth in a stepwise manner It requires a build up of toxin to a certain level before it can affect tumor growth Stalled replication fork can break 0 DNA isomerization allows for different enzymes to be able manipulate the DNA 0 Once can change the chemical nature of any of the binding proteins enzymes etc o All of these changes allow for the speci c enzymes and other process to occur Recombination changes the linkage between speci c alleles and making novel DNA sequences Nonhomologous end joining broken DNA ends just get joined together which can have devastating effects Hemizygous when one allele of the gene is missing Once there is a break the cell recognizes the missing part and nds it in the template strand and copy it to the original breakage to recover the DNA RAD51 bind to broken DNA and search for missing pieces via 3D diffusion until it nds the DNA and then they become 1 Dimensional diffusion dsDNA exonuclease exposes the 3 end of the two strands of the DNA RAD51 binds to the open DNA the incoming DNA strand binds to Watson with Watson and the intermediate is a triple helix Eventually the Watson strands are exchanged Double strand breaks leads to a DECREASE in genetic diversity 12815 Homologous recombination is the only way to recover lost material to a break Unequal sister chromatid exchange Dicentric vs acentric Acentric chromosomes can make spindles Dicentric chromosomes that goes through cell division goes through a mitotic catastrophe Recombination reaches an asymptote at 50 percent because even numbers cancels themselves out Chromosomes have hotspots and cold spots for recombination One can not say that a certain area would have more recombination ratio due to its nucleotide numbers because of hot and cold spot Hotspots have a higher number of recombination compared to the basal level DNA breaks promote recombination Breaks happen in the promoter regions DNA breaks in meiosis happen on purpose due to enzymes which have to be repaired by homologous recombination Finite probability to segregate properly is 1223 22 since this is too low we have to have double stranded breaks so we can have a better chance of getting the right chromosomes for all 23 chromosomes Recombination is a consequence to hold a chromosomes together 0 Regulation of crossover roughly one chromosome per chromosome arm too many crossover doesn t all the chromosomes to separate properly Cell Cycling GZM checkpoint is checking if all the DNA has been replicated and if the chromosomes have separated properly Kinases are a wire and an ampli er 0 Repair proteins send a signal via phosphorylation with kinases that tell the cell not to replicate yet because of the damage 0 If DNA damage is not repaired in a timely manner the sell will go apoptosis 0 A lot of apoptosis causes aging which is what happens with chemotherapy You can repair apoptosis or stop dividing which will eventually die 0 This is mediated by P53 protein 0 Half of all cancers are related to P53 protein
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