Mutagens and carcinogens

Voiceover: So, today we're going to talk about mutagens and carcinogens and how they can cause DNA damage, but first I want to review the central dogma of molecular biology and how the genetic information of a cell is stored in the form of DNA, which is then transcribed to form RNA and then translated to generate protein. Now, nucleotides from DNA are transcribed to their complementary forms on RNA, which are then read as codons, or groups of three, to code for specific amino acids in a larger protein. Now, if you mutate one of the nucleotides on DNA, like turn this thymine base into an adenine base, then that will affect the RNA sequence and ultimately the protein that follows. So, we say that mutations are mistakes in a cell's DNA that ultimately lead to abnormal protein production. So, what is a mutagen? Well, a mutagen is any chemical substance or physical event that can cause genetic mutations. Chemical substances, like certain poisons, could be mutagens or physical events, like UV light or different kinds of radiation could also be mutagenic, and we classify mutagens into two different categories. So, let's say we have a person over here. A mutagen could be classified as endogenous, if it comes from inside this person's body, and it's some mutagen that's already found in the organism, but an exogenous mutation is one that comes from outside the affected organism, something that's from the external environment. So, what are some examples of some endogenous mutagens? Well, the most significant endogenous mutagens are what we call reactive oxygen species or ROS, and ROS are naturally occurring metabolites in the human body that are produced by mitochondria during oxidative phosphorylation. So, if we have this guy here, who's about to chow down on a big meal, you can expect that during the metabolism of the meal, his mitochondria will produce a bunch of ROS, like O2 dot minus, which we call superoxide, which is an oxygen molecule with one extra electron, as well as some hydrogen peroxide, which is another ROS that your body can produce. Now, reactive oxygen species, as you may be able to tell by their name, contain oxygen, like both of these examples do, but they're also highly reactive with different cell components, including DNA, and by reacting with DNA, they can actually cause significant damage to a cell's genetic code. One example of this type of damage is the double-strand break, and ROS can actually break a DNA's double helix into two smaller pieces, and you can see why this type of a reaction could cause a mutation, since it quite significantly changes the structure of the cell's DNA. The next type of DNA damage that ROS can cause is base modification, and that's when the nucleic acid bases are changed or swapped around, and that can pretty readily cause point mutations or maybe even other kinds. Now, you may be wondering why would a cell ever make something that could damage itself? Well, it turns out that ROS actually have a couple of beneficial effects on a cell, and cells actually have a couple of ways to make sure that they don't cause damage, but sometimes ROS levels get really high, and cells can't deal with them anymore, and we call this oxidative stress, and antioxidants are something that your doctor might have told you that are good for you, and it turns out that part of what antioxidants do is help make sure that ROS don't damage your DNA. Now, let's look at a couple examples of exogenous mutagens, and there are many different types of exogenous mutagens, but we're really only going to talk about two. Now, intercalators are one example, and one of them is called ethidium bromide, which you may be familiar with if you've ever done a PCR experiment before, and what ethidium bromide will do is it will jump into a DNA double helix and stick itself between the two strands, and when these intercalators intercalate into DNA, they can deform the structure of the DNA and cause some serious problems. Base analogs, like 5-bromouracil, which we also call 5-BU, pretend to be a certain base, but then act differently than that base normally would. So, in the case of 5-BU, it's an analog of uracil and looks a lot like it, but once it's incorporated into DNA, it can shift between two different forms. In its keto-form, it will pair best with adenine. While it's in enol-form, it will pair best with guanine. Now, if you're familiar with organic chemistry, you might know that 5-BU can convert between its keto and enol form through something called a tautomerization reaction, and overall you can see how this base analog might be able to induce mutations in a DNA strand. Now, the last thing we're going to talk about is what a carcinogen is. Now, carcinogens can be mutagens, but not all of them are, but in general, you can say that a carcinogen is something that can lead to cancer, which, if you remember, is when cells in an organism divide uncontrollably and can form big masses of cells, called tumors. Now, some carcinogens will work by making mutations in DNA that lead to cancer, but sometimes they might carry out their effects simply by increasing the rate at which a bunch of cells divide, without actually affecting their DNA, and some examples of carcinogens are tobacco, which come from cigarettes, asbestos, which used to be used as home insulation, and even UV radiation. So, what did we learn? Well, first we learned that mutagens are chemical or physical substances or events that can increase the probability of genetic mutations occurring. And next we learned that carcinogens are things that lead to cancer, and while they can be mutagenic as well, they aren't necessarily mutagenic.