| Now that we know about the Genetic Code we will be able to understand what a Mutation is. Let´s have a look at a piece of DNA and its decoded Peptide Sequence (Note: the ´O´ in MONEY is usually not a symbol for any amino acid. However, because of this particular example let´s assume it is a symbol for an amino acid. All other one letter symbols represent one amino acid.) This peptide sequence makes perfect sense, doesn´t it? The DNA and peptide sequences as they are shown here would be called wild-type sequences. Now let´s see what can happen to cellular DNA after it has been exposed to the smoke of a cigarette or to burnt meat. Whoops, there is now a mutation which alters the sense of the peptide and gives some nonsense. This mutation would have severe effects on a protein and alter its structure and this would result in a Mutant Phenotype depending on the function of the protein. However, there would be many proteins changes by mutations in many cells if there were not certain protective mechanisms. One of the most important mechanisms, which however, I do not want to further describe at this point is DNA repair. Even the DNA was chemically attacked by mutation inducing agents, there is fortunately a system which can repair this damage before the actual base change has occurred. But don´t challenge this system too much, because not all mutations are repaired if the frequency is too high. Further, there are mutations which would not result in any change of the amino acid as shown in the next Figure. Since in some cases several codons code for the same amino acid a change within these codons would not effect the sequence of a peptide or proteins. Normally this is at the third position of a codon. Another type of mutation, though causing a one amino acid alteration in the peptide does not so severely affect the structure and function of the peptide or protein as demonstrated in this example. Another protective mechanism is the fact that only about 1% of our genome codes for proteins. This reduces the chance that mutations can occur in coding regions. However, mutations occur and the frequency of severe mutations is definitely much higher than the frequency of a certain row of numbers in the lottery. |
| The next question is what consequences mutations can have and why mutations can lead to cancer? Let´s assume a severe mutation has altered a protein with a particular function, for example a protein kinase. Remember, those are enzymes which add a phosphate group to a protein. The effect of the mutation is that this enzyme becomes inactive. Fortunately, nearly all genes exist in two copies because each chromosome exists in two copies. So we have a situation where are normal or wild-type proteins and abnormal or mutant proteins as shown in the figure. Only the wild-type protein is active but not the mutant protein and the Phenotype, meaning the expression of this mutation with respect to the function of the protein is not visible. We call such a mutation recessive. Only when both genes are severely mutated the total function of this protein will be lost. If this was an essential protein for cell survival or growth, the cell will die. However, if this was a protein which when active is important to downregulate growth of the cell under certain conditions, then this cell has lost a regulatory element and is straight on the road to become a cancer cell. Proteins of this kind are called Tumor Suppressor Proteins and their genes are called Tumor Suppressor Genes. We will hear more about those proteins in connection with the ´Cell Cycle´ and ´DNA repair´. |
There is a second type of mutation, which overrides the function of the wild-type protein.
Mutations: Part 2Dominant MutationsLet´s right away continue. In the figure above, you can see a different effect of a mutation. Let´s assume a protein such as for example a receptor, which can only function in the presence of a regulatory substance has a mutation in a regulatory region. The regulatory substance as you have learnt before can be a small molecule or a peptide and this can cause the cell to initiate growth. A mutation in a regulatory region of a protein can override this dependency as shown in the in the figure. Even if we have a wild-type copy of the protein present it would not make any difference, because the mutant protein is continously active. Such a mutation is called dominant and many proteins are known, which when altered by mutation in the corresponding gene are activated continously and stimulate growth promoting cancer. We call these genes Oncogenes. (NOTE: there are dominant mutations, which inactivate a protein and they can also inactivate a protein function by competing with the wild-type protein for a factor.) |
| Transcription factors can be oncogenes too and transcription is our next topic, where we will have a closer look at how the expression of genes is regulated. |
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