We live in a world full of technological devices, instruments and machines. Even if we buy them from good retailers, our cars we use to commute, or our CD-players and nowadays the mp3-players we use to listen to music one day break down, and eventually we change them. Can you imagine a TV which never gets old and can be used forever? The answer is obviously no. But we human beings have a miraculous system that always repairs itself-a system called DNA Repair. The proteins which are produced using DNA as a template, are also used to repair DNA when necessary. Before going into details of DNA repair, let us look at what DNA is, what DNA damage is, and how it occurs.
DNA (deoxyribonucleic acid) is one of four major macromolecules (the others being carbohydrates, lipids, and proteins) that constitute living things. DNA mainly contains genetic information encoded by a combination of four different DNA building blocks, nucleotides, to produce proteins. These proteins in turn play a role in cellular reactions. Genetic material is faithfully copied and passed on from generation to generation, perpetuating the characteristics of the parent and providing children with the information necessary for existence. Our sex, most of our personalities, as well as physical traits (eye color, hair color) are dependent on DNA as a part of the biological order established in our body. Moreover, even aging is a result of the shortening of the packed DNA (chromosome) through time. DNA is crucial for our body, but having such a unique molecule can come at a cost. In particular, cancer and many other disorders are thought to be caused by a lack of proper DNA-handling in cells, due to a defect in DNA repair.
DNA is a fairly stable molecule made up of two strands. Along each individual there are covalent bonds which hold sugar and phosphates together, and the two complementary strands of DNA are bound by hydrogen bonds. But, are these bonds strong enough? Are they unbreakable? To be able to function properly is DNA ever in need of maintenance? Like everything in this world, DNA too can be fragile in extreme conditions (Figure 1). Physical or chemical agents that might cause changes in DNA are commonly known as DNA-damaging agents or mutagens. Mutagens can be either endogenous (like free radicals which are produced from normal metabolic byproducts) or exogenous (like UV radiation or some toxic food chemicals). In addition, DNA can be damaged when synthesizing itself before cell division. These changes may be caused by enzymatic errors or mis-incorporation of nucleotides. Studies have shown that DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell’s ability to carry out its function and appreciably increase the likelihood of cancer formation.
Although there are many ways that DNA can be damaged, we are equipped with DNA repair mechanisms that can reverse the process. As soon as damage occurs to the DNA, it is detected by sensor proteins. These proteins scan the DNA all the time for any bulges or breaks. Once damage is identified the proteins tag it and DNA repair is initiated. A second precaution against damage is provided by a process called DNA Damage Checkpoint (Figure 1). Once this has been activated, cell division is delayed or comes to a halt in order to prevent the change from being passed on to any new cells.
Damage can occur on a single strand or on both strands. Depending on where or how the damage has been introduced, we have different repair systems for each type of DNA damage (Figure 2). In figure 2 we can see the difference between the original, undamaged DNA and the damaged DNA. The DNA repair systems responsible for repairing different defects are also shown in the figure to give a better idea of different DNA repair systems. Of particular interest is the fact that there are more than 150 genes that have been identified to date as being related to DNA repair. When we consider the number of possible defects that can threaten the DNA, this number is surprisingly low in comparison to the total number of genes (~ 30,000 as estimated by the Consortium of the Human Genome Project). Related to that, research in recent years has started to show that the genes which are important for one particular type of DNA repair are in fact required for different repair systems too. When we think about the enormous number of defects introduced into the DNA as opposed to the very few number of proteins involved in DNA repair (as compared to the whole genome), we can easily appreciate the perfection of the system. To give an idea of how DNA is repaired a nucleotide excision repair is shown in figure 3. At the top of the figure, UV exposure causes damage to the DNA. After that, DNA repair is initiated and recognizes the damage. The proteins (represented by circles in different colors) which are responsible for the repair act one after another to bring the DNA back to its original, intact shape.
If damage in DNA is not repaired at all, then the cells with the damaged DNA are either eliminated via a process called apoptosis or mutation occurs. The term mutation refers to permanent changes in the DNA. Although most people assume mutations are harmful, they can be silent or even beneficial depending on the region of DNA in which they occur. In the worst case, when they are deleterious, they can cause many genetically related disorders as well as cancers (Table 1). In this table, we can see different disorders which are caused by lack of appropriate repair systems.
If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and might also result in premature aging. Biologically, aging is an irreversible state in which the cell no longer divides, and is a protective response to the shortening of the DNA ends (telomeres). The telomeres are long regions of repetitive DNA that undergo partial degradation each time a cell is divided. Aging in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell is required by the organism, thus serving as a “last resort” mechanism to prevent a cell with damaged DNA from dividing inappropriately. Since inappropriate division might lead to cancer, the induction of aging and apoptosis is considered to be part of a strategy to protect against cancer.
On the other hand, there is an interesting example for researchers where we see a proficiency of DNA repair activity in an organism called deinococcus radiodurans, the most radiation-resistant organism known to date. Specifically, it exhibits a remarkable resistance to radioactivity (which in turn causes double strand breaks on DNA) most likely due to enhanced DNA repair.
In this article we have tried to answer the question of what DNA repair is, how it is regulated in the cells and what the results of a deficiency in DNA repair are. Studying wonders like the DNA of our biological system is a means of contemplation that leads us to deep reflection on the intricacies of the universe. But one question remains unanswered, how has DNA learned to repair itself?
Hasan Altinbasak is a researcher at the National Institutes of Health.
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