Mutation | CancerQuest
INTRODUCTION. DNA is the chemical found in the nucleus of cells that makes up chromosomes. It is important to all cells, and to all organisms, because. The research aims to determine the relationship between UV-induced DNA damage and the kinds and location of induced mutations and cancer. These are . Cells have a control centre called the nucleus that contains DNA made of genes. Faults (mutations) in some genes can lead to cancer.
The result is that instead of making a single copy of a region of a chromosome, many copies are produced. This leads to the production of many copies of the genes that are located on that region of the chromosome. Sometimes, so many copies of the amplified region are produced that they can actually form their own small pseudo-chromosomes called double-minute chromosomes. The genes on each of the copies can be transcribed and translated, leading to an overproduction of the mRNA and protein corresponding to the amplified genes as shown below.
The squiggly lines represent mRNA being produced via the transcription of each copy of the gene. While this process is not seen in normal cells, it occurs quite often in cancer cells. If an oncogene is included in the amplified region, then the resulting overexpression of that gene can lead to deregulated cell growth.
Gene amplification also contributes to one of the biggest problems in cancer treatment: Drug resistant tumors can continue to grow and spread even in the presence of chemotherapy drugs. A gene commonly involved is called MDR for multiple drug resistance. The protein product of this gene acts as a pump located in the membrane of cells. It is capable of selectively ejecting molecules from the cell, including chemotherapy drugs. This removal renders the drugs ineffective.
Your browser does not support HTML5 embedded video. This is discussed in more detail in the section on Drug Resistance. The amplification of different genes can render other chemotherapy drugs ineffective.
Inversions, Duplications, and Deletions Inversions In these alterations, segments of DNA are released from a chromosome and then re-inserted in the opposite orientation.
This is different from gene amplification in that the genes are not replicated outside the chromosome and they are only copied one extra time, not hundreds or thousands of times. Genes may also be lost due to failure of the replication process or other genetic damage. Aneuploidy Aneuploidy is the genetic change that involves the loss or gain of entire chromosomes.
Due to problems in the cell division process, the replicated chromosomes may not separate into the daughter cells accurately. This can result in cells that have too many chromosomes or too few chromosomes. An example of a fairly common aneuploid condition that is unrelated to cancer is Down syndrome, in which there is an extra copy of chromosome 21 in all of the cells of the affected individual.
The relationship of DNA methylation to cancer.
In the animation below, copies of two chromosomes are made but when the cell divides the chromosomes are not distributed evenly to the two cells that are formed daughter cells. The result is that one of the cells has too many chromosomes and one does not have enough. Cancer cells are very often aneuploid.
Humans normally have 46 chromosomes in their cells, but cancer cells often have many more, sometimes greater than The presence of the extra chromosomes makes the cells unstable and severely disrupts the controls on cell division. There is currently an ongoing debate as to whether or not all cancers are aneuploid. Regardless of whether that is the case, it is clear that aneuploidy is a common feature of cancer cells.
Epigenetic Changes In addition to actual alterations in DNA sequence, gene expression can be altered by changes to the DNA and chromatin that do not change the sequence. Methylation In this alteration, some nucleotides in the DNA are modified by the addition of a methyl -CH3 group to the base.
Abnormal DNA methylation patterns have been seen in cancer cells. Like the changes described, methylation alters the expression of the affected genes.
This alteration leads to a loosening of the DNA: The modification of the processes of addition and removal of acetyl groups to DNA is an active area of cancer treatment research. More on epigenetic changes and cancer treatments. The mechanisms by which the changes are induced is varied. Spontaneous Mutations Spontaneous mutations: For example, the loss of an amino group from cytosine, a normal base found in DNA, leads to the production of uracil, a base not normally found in DNA.
If this change is not detected and reversed, a mutation can result. Occasionally, an entire base can be lost as a result of the cleavage of the bond between the DNA backbone and the base. This leads to a gap in the DNA double-helix, which, if not repaired, can lead to a mutation the next time the DNA is copied i. Induced Mutations Induced mutations: Mutations can be induced by exposing organisms or cells to a variety of treatments.
Genes, DNA and cancer | Cancer Research UK
Some of the most common are: Radiation- One of the first known mutagens, radiation is a potent inducer of mutations. Different types of radiation cause different types of genetic changes. Ultraviolet UV radiation causes point mutations. X-rays can cause breaks in the DNA double-helix and lead to translocations, inversions and other types of chromosome damage. Exposure to the UV rays in sunlight has been linked to skin cancer. Note that the DNA damaging properties of radiation have been utilized in several different radiation-based cancer treatments.
Shown below is a type of mutation that is caused by ultraviolet radiation. In this example, the bombardment of the DNA double-helix by UV rays causes two bases to join together. This alters the structure of the DNA and can lead to permanent changes if not repaired. Another type of radiation is the energy emitted by naturally occuring radioactive elements like radon and uranium or man-made sources like those found and created in nuclear reactors.
Radiation of this type comes in different types and can cause different types of damage to cells and tissues. Radiation can directly damage DNA or can cause the formation of chemicals i. Exposure to radiation from radioactive materials has been well documented. Analyses of survivors of the atomic bombs dropped on Japan during World War II showed large increases in leukemias shortly after the exposure and then increases in other cancer types over the following decades.
Radiation exposure due to the accidental release of radioactive materials from the Chernobyl nuclear reactor have been associated with increases in thyroid cancer and other malignant cancers. The amounts used for any single test are not thought to cause siginificant amounts of cancer, but the long term impact of many tests over a period of years is not clear.
These chemicals exert their effect by binding to DNA or the building blocks of DNA and interfering with the replication or transcription processes. Some examples of potent mutagens are benzo-a-pyrene, a chemical found in cigarette smoke, and aflatoxin, a mutagen most often found on improperly stored agricultural products. An example would be the long-term inflammation caused by infection with the hepatitis virus. Learn more about viruses and cancer. Oxygen Radicals- During the capture of energy from food, which occurs in our mitochondria, chemicals may be generated which are very reactive and are capable of damaging cell membranes and DNA itself.
These reactive oxygen intermediates ROI may also be generated by exposure of cells to radiation, as shown below. The mutagenic activity of ROI is associated with the development of cancer as well as the activities of several anticancer treatments, including radiation and chemotherapy.
The cells will either be missing, or have gained a significant number of genes. This rare process can create cells that are more prone to unregulated cell division. As stated previously, a large percentage of cancers isolated from humans are aneuploid.
If a cell has a mutation in a gene whose protein product is responsible for 'checking' on the division process, things can rapidly get out of control and the daughter cells of each division can become increasingly abnormal. Viruses as Mutagens Viruses are thought to be responsible for a significant percentage of cancer cases. Viruses can cause cancer in a variety of ways and the way that each type of virus works is likely to be slightly different. Some viruses including many retroviruses can cause mutations by inserting their genes into the genome of the infected cell.
The inserted DNA can destroy or alter the activity of affected genes. An infection with hepatitis virus can last for many years. During that time the body's defense system tries to get rid of the virus by producing toxic chemicals. Those chemicals can cause damage to otherwise healthy 'bystander' cells, sending them down the road that leads to cancer.
There are numerous other ways that viruses can cause cancer. Transposons encode an enzyme, transposase, that acts to splice the transposon into new locations in a genome see schematic, below left, of a transposon Transposons were discovered by Barbara McClintock and she won a Nobel prize for her work. A visible example of transposon movement called transpositionis the coloration of the kernels in Indian corn see below right.
The transposons that are active in humans are thought to be involved in human disease, including cancer. Most cancers are thought to arise from a single precursor cell that acquires sufficient mutations to become a cancerous cell.
DNA Mutations Genetic changes can be small, affecting only one or a few nucleotides point mutations or they may be quite large, alter the structure of a chromosome or chromosomes. The mutations are grouped according to the changes they create in the resulting protein product of the affected gene. Nonsense mutations - The new mutant codon causes protein synthesis to stop prematurely.
Missense mutations - The altered codon results in the insertion of an incorrect amino acid into the protein. Sometimes mutations in important genes cause a cell to no longer understand instructions. It doesn't repair itself properly, and it doesn't die when it should. This can lead to cancer. There are 4 main types of genes involved in cell division.
Most tumours have faulty copies of more than 1 of these types. Usually in adults, this would not happen very often. When one becomes damaged, it is like the accelerator pedal becoming stuck down. So a cancer develops.
Genes that stop the cell multiplying tumour suppressor genes Usually, cells can repair faults in their genes. The best known tumour suppressor gene is p But cells contain many different proteins whose job is to repair damaged DNA. Thanks to these proteins, most DNA damage gets repaired immediately, with no ill effects.
So errors will build up in other genes over time and allow a cancer to form. Genes that tell a cell to die self destruction genes Some genes normally tell a cell to self destruct if it has become too old or damaged. This is called apoptosis or programmed cell death. It is a highly complex and very important process.