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Mechanisms of DNA Damage and Repair
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Professor Dave again, let's learn about the mechanisms of DNA damage and repair. As we've learned, your DNA is the template from which everything inside you is built, so it's incredibly important that nothing happens to this code. But your DNA is constantly at risk of mutation, which means a change to the genetic information in a cell, and this can happen due to a variety of factors. Let's learn about some of the different ways that mutations arise and what your body can do about it. First let's make the distinction between large-scale mutations, where a whole chunk of a chromosome is lost, relocated or rearranged, vs. point mutations. A point mutation is typically a change in just one base pair in a DNA molecule, and believe it or not a difference of even just one nucleotide can be enough to cause major problems in the body. Let's recall our prior example, sickle cell disease. This is a genetic disorder that results because of a difference in a single nucleotide in the DNA of a carrier when compared to the DNA of a non-carrier. This difference occurs in the gene that codes for one of the subunits of hemoglobin, the protein that carries oxygen through the bloodstream. In this gene there is an A where a T should be in the template strand of the gene, which will code for U instead of A in the corresponding mRNA, and then this altered codon will code for valine instead of glutamic acid. The hydrophobic side chain on valine is different enough from glutamic acid that the mutation results in a conformational change, which in turn causes hemoglobin to aggregate in low-oxygen conditions, forming hemoglobin fibers. As a result, the red blood cells that carry hemoglobin will be distorted into a rigid, sickle shape. These can clog small blood vessels, which is a serious condition, so we can clearly see that even one point mutation can be disastrous for an organism. When there is a point mutation one possibility is that a nucleotide pair substitution occurs. The mutation that causes sickle cell disease is an example of this, where one base pair is replaced with a different base pair. If this occurs outside of a gene, it is unlikely to have any effect, because these portions of the chromosome do not code for anything, but if this happens within a gene, it can have a few different results. If the resulting change in the template strand results in a new mRNA codon that translates for the same amino acid as before, which is possible, since multiple codons can sometimes code for the same amino acid this is called a silent mutation. In this case, even though there was a change in the gene, the resulting protein will not be any different. If the change in the mRNA codon translates for a new, different amino acid, that is called a missense mutation, which is the most common point mutation. This often won't make a big difference either, as many of the amino acids have similar side chains and changing just one amino acid may have very little impact on the overall shape and behavior of the protein, but we saw with sickle cell disease that once in a while a missense mutation might make a big difference. Among other reasons, this can be true if the amino acid that changed was the key residue in supplying the catalytic activity of an enzyme. The active site might change shape due to new repulsive interactions, rendering it unable to bind its substrate, or maybe the side chain on this residue was specifically needed to do chemistry on the substrate, which now can't happen in its absence, and if that enzyme can't do what it normally does, it could be a big problem for the cell. So missense mutations, while often benign, have the potential to be extremely harmful. Lastly, it is possible that a substitution of this nature could cause the corresponding mRNA codon to no longer code for an amino acid, but to instead become a stop codon. We call this a nonsense mutation. This means that instead of the ribosome translating the rest of the mRNA strand it will just stop entirely, resulting in a partially complete protein. Unless the new stop codon is extremely close to the intended stop codon, it is highly unlikely that this protein fragment will be able to perform its intended function. Sometimes, instead of substitution, there can be insertion or deletion. As you might guess this is where one base pair is inserted or deleted from the DNA sequence. These kinds of mutations will typically have enormous impact on the resulting protein because the codons on the resulting mRNA are supposed to be translated as groups of three nucleotides. If one of these is suddenly added or deleted, every single codon after this mutation will be altered, resulting in a huge number of missense mutations, and most likely an eventual premature stop codon. These are called frameshift mutations, because the entire reading frame of the genetic code gets shifted. Frameshift mutations almost always result in a non-functional protein. Now that we are sufficiently terrified of genetic mutations, what is it that causes them to happen? Our thoughts may turn first to a glowing green ooze, but that's just a cliché. Let's learn about the real causes of mutation. The first source is called spontaneous mutation. This is when the cellular machinery simply makes a mistake by itself, as not even mother nature is perfect. Once in a while, polymerase will make a mistake during replication, placing the wrong base across from the template strand. Usually it will correct itself but sometimes it will leave the error in, like for example this G across from a T on the template strand. This mismatch can be recognized by one of a variety of DNA repair enzymes that scan DNA hunting for these kinds of errors, and they know exactly which base to kick out and which base to replace it with. This is called DNA mismatch repair. But the chromosomes are so incredibly long that even these hard-working repair enzymes might miss an error. If this DNA molecule is used as a template for further replication, this strand here will do just fine, since nothing happened to it, but when replicating this strand, the G was actually supposed to be an A so instead of coding for the T that is supposed to go across from it it'll code for C instead, and the GC pair that results won't look any different from any other GC pair in the molecule, so no repair enzyme can ever recognize it, and the mutation can never be fixed. This type of spontaneous mutation will happen around once in every ten billion base pairs, which gives us pretty decent odds, and hopefully when it happens it's in some random location in the chromosome where it won't make a difference, but if it's in a gene, who knows. Now it's not just our heroic enzymes that are at fault, there are external causes of mutation too, which we call mutagens. One such mutagen is radiation. Photons of light from the ultraviolet portion of the electromagnetic spectrum are high-energy particles, and if they collide with DNA in specific locations they can cause pyrimidine dimers. This is when two adjacent thymine or cytosine bases become covalently linked, which distorts DNA, making normal genetic activity impossible. Luckily this distortion, or lesion, can be recognized by a repair enzyme that will initiate nucleotide excision repair. A nuclease enzyme can spot the problem and snip out a section of the DNA strand containing the lesion. Then polymerase puts new bases in the gap, and ligase seals it up. Good as new. So this is why UV light from the sun can be harmful, it may cause mutations like pyrimidine dimers. X-rays and gamma rays can cause mutations too, since they are also comprised of high-energy photons. Other mutations involve modifications to a singular base. These are caused by chemical mutagens like certain oxidizing agents. For example, guanine can be oxidized to become 8-oxoguanine, or oxoG. And because of the difference in orientation and functionality, oxoG does not pair with C like a normal G does, it pairs with A instead. If this error is not fixed and the opposite strand is used as a template for replication, once again the polymerase will have no way of knowing that this A was supposed to be a C, so instead of the G that ought to go on the complementary strand it'll put a T and the mutation can no longer be fixed. Other such modifications arrive in the way of alkylating agents, which add things like methyl groups to existing bases, which will interfere with replication and transcription. These types of mutations do not cause kinks in the DNA strand like thymine dimers do so they are not recognized in the same way that nuclease enzymes operate. These are instead recognized by glycosylase enzymes that will initiate base excision repair. This is different from nucleotide excision repair in that the enzyme specifically recognizes the mutant base, flips that nucleotide out of the helix and removes the base by snipping the glycosidic bond, which is why the enzyme is called a glycosylase. Then polymerase and ligase do their jobs to put things back together. There is a different glycosylase for each kind of mutation of this variety and they are all constantly scanning DNA for errors. So these are a few examples of the kinds of damage that can occur in DNA, and while there are many more most of them fall into one of these categories according to the type of enzyme that can repair them. We have enzymes that can do mismatch repair, ones that do nucleotide excision repair, and others that do base excision repair, and there are over 100 different types of DNA repair enzymes in every cell in your body, keeping constant vigil over the sacred genetic code. Even still, let's give him a break once in a while, make sure you wear your sunscreen when you go to the beach. Thanks for watching, guys. Subscribe to my channel for more tutorials, and as always, feel free to email me:
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