DNA Damage and Repair

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BIOLOGY OF AGING

DNA Damage and Repair An introduction to aging science brought to you by the American Federation for Aging Research DNA BASICS metabolism in cells can produce WHY IS DNA REPAIR toxic molecules called reactive IMPORTANT? DNA stands for deoxyribonucleic oxygen species, a class of ”free acid. The nucleus of each human radicals.” These substances can In both dividing and non-dividing cell contains forty-six structures react with and modify the bases cells, DNA is vital to their every- called chromosomes that together in DNA and prevent the code from day functioning. The code in DNA “package” all our genetic informa- being used properly. In fact, the is read by special enzymes and tion or genes. This information is DNA in each cell of our bodies “translated” into the proteins that coded by a series of four bases: probably sustains at least 10,000 carry out all of our cellular and adenine, guanine, cytosine, and injuries or errors each day! If DNA other bodily processes. Even small thymine. These are linked together is like a zipper, free radicals pro- errors in DNA sequence can have in a specific sequence or code. In duce stray threads or distorted serious effects. A single unrecog- addition, each strand of code has teeth that can jam and break the nized and uncorrected DNA error a complementary strand in which zipper. Exposure to toxins, such as can disable a critically needed the bases are paired: adenine ultraviolet light or cigarette smoke, protein and, over time, result in pairs with thymine and cytosine can also damage DNA. And the disease or even death. pairs with guanine. The base pairs enzymes that make new DNA are like rungs in long, twisting, Our cells must have the ability (which happens just before a cell to repair lesions in their DNA to zipper-like genetic ladders. These divides) occasionally make mis- base pairs create the sequences, survive. If the DNA of dividing takes. They can accidentally insert cells is sufficiently damaged, the or instructions needed to form our improper base pairs, resulting in bodies. DNA cannot be properly copied, DNA mutations. Erroneous repair and the cells cannot divide. Genes are portions of this genetic of DNA damage during replication Instead, they turn into senescent material critical to growth and is quite common. (dysfunctional and no longer reproduction. They also have DNA REPAIR dividing) cells or simply die. important day-to-day functions. Alternatively, the DNA damage can For example, genes carry the Of course, DNA damage needs be fixed and the chemical integrity instructions for making proteins, to be repaired. And our cells have of the DNA molecule restored, but enzymes, and others substances evolved a sophisticated system due to partial infidelity of the repair that in turn carry out many cellular of recognizing the multitude of mechanisms the original genetic processes, such as energy genera- possible chemical lesions in DNA code can be altered, resulting tion and hormone creation. All of and fixing them. To return to in a mutation. Mutations are our cells, except sperm and eggs, the analogy of DNA as a zipper, permanent changes in the genetic contain two copies of each gene. picture our cells as having tiny code, which, unlike DNA damage, That is, all the genes we need are scavenger proteins that spend cannot be recognized and fixed by encoded by 23 chromosomes, but all of their time searching for and the DNA repair mechanisms. our cells contain a duplicate copy eliminating stray threads and of each chromosome—or a total foreign matter and broken teeth The genes in the nuclei of our cells of 46. that have made their way into our are not the only sources of DNA DNA zippers. This process in our cells. Cells also contain DNA can be damaged in several of weeding out such damage is many tiny organelles called ways. For example, energy DNA repair. mitochondria. Mitochondria act as

2 | Infoaging Guide to DNA Damage and Repair powerhouses for our cells, trans- substantial number of our genes mismatch repair systems to forming oxygen and other fuels are devoted solely to repair of ensure that no errors have been into the energy we need to live. DNA damage. Researchers have made that would result in muta- Mitochondria possess their own outlined the steps involved in tions. Nevertheless, errors do DNA, and they use it to produce repairing damaged or mismatched occasionally occur and cannot be the proteins that carry out energy bases in DNA within human cells. avoided. production. Because mitochondria They are: use oxygen in energy production, SINGLE STRAND AND DOUBLE their DNA is surrounded by free • Recognition of the damage STRAND BREAKS radicals (the toxic byproducts • Uncoiling the segment of DNA Occasionally, the DNA strand of energy production), and this with the damage greatly increases the amount of is actually broken. This can be damage their DNA can sustain. For • Making a snip in the DNA on caused by chemicals or free many years, scientists believed either side of the damaged radicals, and particularly by certain that mitochondrial DNA had no piece forms of radiation. If the break effective repair mechanisms. More occurs in one of the two strands, recent research has shown that • Removal of the damaged that is called a DNA single-strand some mitochondrial DNA repair segment break. These can be repaired by systems do in fact exist, but they processes similar to those that • Recreation of the tiny piece of repair damaged or mismatched are much less effective than those DNA that was damaged using in the nuclei. This may be a reason bases; the broken pieces are the undamaged DNA strand eventually “glued” back together. why the mutation rate in mitochon- for instructions to recreate the drial DNA is much higher than that proper nucleotide sequence When both strands are broken, of nuclear DNA. the result is called a DNA double • “Gluing” the new, correct bit strand break. These are the most HOW DOES DNA REPAIR of DNA back into the whole potentially catastrophic types of WORK? strand DNA damage. Imagine the struc- For any creature to survive, it Actively dividing cells, which are tural damage when both vertical must be able to reproduce its more vulnerable to errors during shafts of a ladder are broken. DNA faithfully. For example, a repair, have “proofreading” and Our cells, however, can still repair this damage through an intricate,

Our cells must have the ability to repair lesions in their DNA to survive.

Infoaging Guide to DNA Damage and Repair | 3 multi-stage process. Each step • Animals with the highest rates study that looked in white blood requires a different DNA repair of oxidative damage by free cells found DNA damage in two protein, and successful repair radicals (and specifically, with to four percent of the cells from requires that all of these proteins oxidative damage to DNA) young adults, but six times more work correctly, in the proper order. generally have the shortest life often in cells from the elderly. It is a complex, almost miraculous spans. These aging white blood cells with piece of work. However, some- their higher level of DNA damage times when there are multiple • In lower life forms subject to may explain some of the decline in double-strand breaks in a cell, the oxidative damage, antioxidant immune function associated with wrong ends are annealed, resulting supplements, which can aging. in the type of chromosomal correct and prevent DNA alterations often found in cancer. damage when it occurs DNA damage also contributes to Scientists have also recently naturally, do increase life the development of age-related discovered that certain sequences span. This has been shown in diseases, such as heart disease, of junk DNA called retrotranspo- worms, insects, and rats. lung cancer, and atherosclerosis. sons can jump into the breach of a DNA damage from cigarette • Exposure to external causes of smoke is a primary culprit in each DNA double strand break, knitting DNA damage (ultraviolet light, it together again. of those diseases. In addition, tobacco) decreases life span. oxidative damage is also linked to HOW DO DNA DAMAGE AND • Humans who have genetic Alzheimer’s disease and macular REPAIR RELATE TO AGING? diseases resulting in greater degeneration. spontaneous DNA damage WHAT CAUSES DNA DAMAGE? Some scientists believe that the or inefficient DNA repair often accumulation of uncorrected DNA show signs of premature aging. Causes of DNA damage fall into damage over years is a major two broad categories: natural cell cause of aging. They cite the Several different types of cells processes and external causes. following observations: taken from elderly subjects show evidence that DNA repair declines • Animals with the fastest rates Natural cell processes and DNA damage accumulates The creation of energy in a cell of DNA repair generally have with age. Elderly patients’ blood the longest life spans. utilizes oxygen. In addition to and skin cells have less capacity energy, that process produces to repair themselves than those toxic byproducts called reactive from young adults. Indeed, one oxygen species. These are a class of free radicals, which can damage DNA as well as cellular proteins and fats.

Scientists believe that the External causes Ultraviolet light has been accumulation of uncorrected recognized as a cause of DNA DNA damage over years is a damage for nearly 25 years. major cause of aging. X-rays can break the strands of DNA in cell nuclei. Toxins like benzo[a]pyrene, medications like those used in chemotherapy, and that most deadly poison, cigarette smoke, all cause DNA damage.

4 | Infoaging Guide to DNA Damage and Repair Researchers are exploring why some people age more successfully than others. They are looking at the genes that govern DNA repair and asking if there are some versions of those genes that offer greater benefits than others. Photo courtesy National Cancer Institute.

HOW DO DNA DAMAGE AND cells have acquired mutations design chemotherapeutic drugs REPAIR RELATE TO CANCER? in their DNA that permit them to that might reverse or prevent those bypass the normal limits of cell abnormal methyl group insertions. Most normal somatic (body) cells division. They become immortal One such drug is decitabine, and in humans have limited repro- and reproduce indefinitely as it has indeed been shown to have ductive life spans. Most somatic tumor cells. Cancer-causing efficacy in certain blood cancers. cells that continue dividing after DNA mutations also include the birth can only reproduce so many loss of genes that act as tumor Inherited cancers times. When cells can no longer suppressors and the activation Some cancers run in families. divide, they become dysfunctional, of oncogenes, which promote Some of these inherited cancers or senescent. Some senescent cancer. can be traced to a DNA error cells die, whereas others may called base-pair mismatch, in accumulate in aged tissues. Cells The abnormal insertion of methyl which the subunits of DNA get that don’t divide after birth, such groups into DNA at the regula- lined up improperly. Normal cells as brain and heart cells, eventually tory portion of certain genes has have efficient mismatch repair senesce and die as well. been noted in many cancers, systems; a few of us inherit particularly those that arise in the DNA damage followed by inef- defective genes for mismatch blood cells. This observation has repair, and thus are prone to fective repair has been linked to prompted researchers to try to several types of cancer. Cancer certain cancers. This is one of

Infoaging Guide to DNA Damage and Repair | 5 nature’s ironies: an inherited type Most cancers arise from the accu- Researchers are also exploring of DNA damage paves the way for mulated mutations in our somatic why some people age more later acquired DNA mutation and cells caused by years of exposure successfully or later than others. cancer. to external toxins. One of the most They are looking at the genes that deadly of these toxins is cigarette govern DNA repair and asking if Sometimes people inherit a smoke. Cigarette smoke has been there are some versions of those susceptibility to damage by extensively analyzed and found genes that offer greater benefits certain environmental agents. For to contain hundreds of potential than others. This phenomenon, example, albinos have inherited an cancer-causing substances. called polymorphism, refers to the absence of skin and hair pigments. Many of these toxins damage fact that genes come in different They are unprotected from sunlight DNA by attacking the bases, variants. Think of the genes for eye and ultraviolet light, which cause creating DNA adducts (large, color—they appear on the same DNA damage. disruptive molecules that muck spot on each of our chromosomes, Some cancer may be the result up DNA). Interestingly, cells in the but some of us inherit a gene for of inadequate DNA repair. Certain lungs have been found to be less blue eyes at that spot, others genetic diseases that feature efficient at repairing and removing for brown. Similarly, some of us diminished DNA repair capac- DNA adducts than other cells in probably inherit genes that pro- ity are associated with high rates the body. This allows the number mote accurate and successful of cancer. For example, patients of lung cells with DNA adducts to DNA repair, while others inherit with xeroderma pigmentosum, rise, which may eventually lead to less robust DNA repair systems. cancer. an inherited disorder resulting As scientists develop a greater in reduced DNA repair, have a understanding of the processes predisposition to skin cancer. HOW ARE SCIENTISTS STUDYING DNA DAMAGE of DNA damage and repair, they Accumulating evidence also AND REPAIR? will also pursue research into suggests that some breast controlling those processes. An cancers may be due to an With the recent decoding of the exciting area of research will be inherited insufficiency in DNA human genome, research into the development of treatments repair. About half of all inherited human DNA damage and repair that can reduce the rate of DNA cases of breast cancer are linked continues at the forefront of damage and other treatments to a mutation in the gene BRCA1. science. Among the areas that that can improve the efficiency Scientists exploring the role of the intrigue scientists is in-depth and accuracy of DNA repair non-mutant form of BRCA1 have research into the premature mechanisms. found the protein seems to play an aging syndromes such as Werner important role in triggering repair syndrome. Scientists are learning of broken strands of DNA. how the genes that relate to this and other syndromes like it act, Externally caused cancers realizing that understanding the Not all cancers arise from a DNA genetics of premature aging may mutation that we have at birth. also lead to understanding the genetics of normal aging.

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