Skip to 0 minutes and 14 secondsCancer is a genetic disease associated with the loss of control of the cell cycle. The information necessary to control the cell cycle is encoded within the genetic material, the DNA. And cancer occurs when cells acquire mutations in genes controlling multiple aspects of cell cycle control. Although some individuals inherit mutations that predispose to familial cancers, most of the mutations that occur in the tumours of both sporadic and familial cancer patients, arise during the lifetime of the individual. A copy of the genetic material is present in every cell and is essential for the functioning of all cells. The human genome controls not just how and when cells divide, but every aspect of cellular tissue and organismal physiology.
Skip to 0 minutes and 57 secondsThus, it is not surprising that natural selection has allowed us to evolve cellular systems that minimise, as far as possible, the occurrence of DNA mutations. Fortunately, the complimentary nature of the DNA double helix, helps the cell reduce the frequency with which errors arise. Nonetheless, the challenge facing the body in trying to preserve its DNA is immense. The human genome is very large. The genome contains approximately 6 billion base pairs of DNA. And every cell acquires a copy of this information. Thus, the first challenge that faces us, is copying the single copy of the human genome present in the fertilised egg and replicating a copy of this into the trillions of cells present in an adult human.
Skip to 1 minute and 38 secondsSo one of the most important insights that was gained by Watson and Crick when they discovered the structure of DNA, was the complimentary nature of the base pairs. In the DNA double helix, G bases are always paired with C bases. And A bases are always paired with T bases. This provided an immediate explanation as to how cells could replicate their DNA. By separating the duplex into two new template strands and copying the information on each strand into two new daughter strands, it is possible to generate two new duplexes. Wherever there is a G on the template strand, there should be a C on the daughter strand and vice versa. And similarly for As and Ts.
Skip to 2 minutes and 19 secondsIn cells, the synthesis of DNA is carried out by an enzyme called DNA polymerase. This enzyme is very accurate and makes a very few mistakes. Only about one in every 30,000 bases copied is incorrect, putting a C opposite an A, for instance. I would be very pleased if my typing was that accurate. However, the challenge facing DNA polymerase is huge. And when the entire genome is copied, DNA polymerase makes about 200,000 mistakes. Clearly, if all of those mistakes were allowed to persist, the genome would quickly disintegrate. Fortunately, we have evolved a DNA repair system called DNA mismatch repair that is able to repair the vast majority of these misincorporation errors.
Skip to 3 minutes and 2 secondsBy referring to the template strand, the DNA mismatch repair machinery can correct the daughter strand, meaning that DNA is usually copied very accurately from one cell to the next.
Skip to 3 minutes and 15 secondsThe importance of the DNA mismatch repair pathways is illustrated in the type of inherited cancer, called hereditary nonpolyposis colon cancer. In this type of familial cancer, individuals inherit a mutation in one of their DNA mismatch repair genes. In cells in which a second hit occurs, knocking out the other copy of the DNA mismatch repair gene, the accuracy of DNA replication is much lower than normal and cells can quickly acquire the multiple mutations necessary to change from a normal cell to a cancer cell. The most common type of cancer in this syndrome is colon cancer.
Skip to 3 minutes and 48 secondsAnd this is thought to be because of the very high rate of cell division and hence DNA replication that is necessary to maintain the gut epithelium. Once the DNA has been replicated correctly, you might think that the danger is over. Unfortunately, this is not the case as DNA is a relatively unstable molecule and is prone to acquire additional damage in the form of various types of lesions, including breaks in the DNA strands and losses and chemical modifications of the individual bases. Most of this damage either occur spontaneously or as a result of the byproducts of cellular respiration. Cells produce energy by combining carbon and hydrogen with oxygen to produce water and carbon dioxide within the mitochondria.
Skip to 4 minutes and 32 secondsThis is the same chemical reaction as occurs when we burn something but is usually much more tightly controlled within the mitochondria. Nonetheless, oxygen free radicals can be generated as a byproduct of this process. And these molecules are very damaging toward DNA. DNA damage such as this is very common and every cell acquires hundreds of thousands of such lesions every day. Fortunately, most of these, such a single stranded breaks and base losses are very easy for the cell to fix. However, some types of DNA damage, such as base modifications, are more difficult to fix. Fortunately, we have also evolved other DNA repair pathways that can correct most of this type of damage.
Skip to 5 minutes and 13 secondsThese pathways also take advantage of the double stranded and complimentary nature of the DNA sequence, to correct any defects in one strand by reference to the complimentary sequence on the other strand. In addition to this endogenous source of DNA damage, cells can also be exposed to exogenous sources of DNA damage, such as the chemicals found in cigarette smoke and the damaging consequences of radiation. Again, most of this damage is also fixed by the DNA repair machinery but if the level of exposure is too high, then some lesions are not fixed and mutations arise. This increase in the mutation frequency, underlies the strong association with genotoxic exposure in cancer.
Skip to 5 minutes and 54 secondsSimilarly, as with DNA mismatch repair, inherited mutations in the other genes associated with DNA repair are associated with cancer predisposition syndromes, showing extreme sensitivity to environmental carcinogens. Thus, to prevent cancer the human genome must be faithfully replicated and maintained intact throughout life in every cell, despite the fact that it's under constant attack from endogenous and exogenous chemicals. Fortunately, active DNA repair corrects most replication errors in DNA damage. These efforts are not fully effective though and individuals who inherit mutations in DNA repair genes or who are exposed to genotoxic agents, have an increased cancer risk.
Keeping the genome in good shape
Professor Darren Monckton introduces us to the concept of how DNA can be damaged and how our cells cope with this. In this video you will see a pedigree or family tree. More information on drawing a family tree is given in steps 3.14-3.16. After this video there will be a short quiz to enable you to test your understanding.
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