DNA Damage and Repair in Skin Aging

  • Daniel B. YaroshEmail author
Living reference work entry

Later version available View entry history


Skin aging reflects the accumulation of damage to DNA from both internal and environmental sources. While solar UV induces the most frequent modifications of DNA, air pollution and tobacco smoke have also been demonstrated to induce the cascade of repair responses triggered by DNA damage. Cells use complexes of proteins to remove or reverse DNA damage, but if the lesions are not repaired, a sequence of proteins is activated that invokes wound-healing reactions or cell death. If these reactions are not sufficient to control the DNA damage, the skin risks immunosuppression, destruction of the collagen support structure, and even cancer. Genetic mutations in DNA repair genes can cause hereditary cancer diseases, while simple polymorphisms in some DNA repair genes in apparently healthy people may also predispose them to cancer. Methods to defend against DNA damage include melanin, sunscreens, antioxidants, and administration of DNA repair enzymes.


Reactive oxygen species (ROS) 8-Oxoguanine (8oxoG) Cyclobutane pyrimidine dimer (CPD) 6-4-Photoproduct <6-4 > -PP Air pollution Tobacco smoke PM2.5 Nucleotide excision repair Base excision repair Photoreactvation Nicotinamide adenine dinucleotide (NAD) Xeroderma pigmentosum Trichothiodystrophy Cockayne Syndrome Solid organ transplant NFAT Melanin Sunscreens Antioxidants DNA repair enzymes T4 endonuclease V Wound healing Photoaging 


DNA has many roles in skin cell function, including directing metabolism, storing the information of heredity, and sensing cell danger. Damage to DNA is correlated with, and probably a major cause of, aging in general and skin aging in specific [1]. Our natural repair system offers significant protection, and new compounds offer the promise of augmenting DNA repair.

This chapter will focus to a large extent on UV damage to DNA because solar UV is by far the greatest danger to DNA. Sun exposure is a major public health concern and has been directly linked to most of the more than 3.5 million new skin cancers that arise in the USA each year [2]. Over the past 20 years, the incidence rates of nonmelanoma skin cancer and melanoma have consistently increased [3]. DNA damage caused by solar UV has been directly linked to these skin cancers, as the cancers contain in their inactivated tumor suppressor gene mutations that are characteristic of UV [4]. Other important contributors to DNA damage that cause skin aging are tobacco smoking and air pollution.

Sources of DNA Damage

DNA damage comes from two sources: the intrinsic metabolism of the cell and environmental insult.

Intrinsic Metabolism. During aerobic energy generation, about 2 % of all the oxygen burned ends up as reactive oxygen species (ROS). DNA is damaged by ROS most frequently by the oxidation of the guanine base to form 8-oxoguanine (8oxoG) , which is often misread by the DNA replication machinery causing a mutation. This is particularly serious for mitochondria, whose DNA is closest to the source of the short-lived ROS. Stress, caused by, e.g., long working hours, is associated with increased levels of 8oxoGua in urine [5]. In addition, disruption of the circadian rhythm by our modern lifestyles and normal aging can also increase the accumulation of DNA damage by disrupting DNA repair [6].

Environmental insult. By far the most serious damage to skin DNA is from the sun, because DNA readily absorbs photons in the UV region producing modified DNA bases. These modified bases cause a characteristic type of DNA mutation produced by no other carcinogen, and these signature mutations are frequently found in key cancer genes in squamous and basal cell carcinomas. This is the smoking gun that connects sun exposure to this sign of premature aging. Solar UV may indirectly damage DNA by creating reactive oxygen species that then react with DNA. Additional environmental sources of DNA damage to skin come from pollutants carried in the air, particularly in urban areas.

Sun Damage to DNA

Wavelengths of Sunlight that Damage DNA

DNA readily absorbs photons in the UV portion of the solar spectrum. Although the shorter UVC wavelengths (200–280 nm) do not actually reach the earth’s surface due to their absorption by the ozone layer, the longer-wavelength UVB (280–320 nm) is still relatively efficient in causing direct damage to the DNA bases and penetrates largely only into the epidermis [7]. The even longer-wavelength UVA (320–400 nm) penetrates into the dermis; however, since these photons carry less energy, they are relatively less efficient in producing direct damage to DNA than UVB and create proportionately more reactive oxygen species in the skin cells that indirectly damage DNA [8]. Recent evidence suggests that very high fluences of visible light can produce indirect DNA damage through the formation of reactive oxygen species [9].


Solar UV directly causes an instantaneous photochemical reaction in DNA that links together adjacent pyrimidine bases (cytosine or thymine) [10]. This cyclobutane pyrimidine dimer (CPD) is the most common form of DNA damage and is formed by all UV wavelengths, including UVA, UVB, and UVC [11]. After a sunburn dose, on the order of 100,000 CPDs are formed in the DNA of every sun-exposed cell. In a much less common reaction, solar UV can directly link together these bases by a single twisted bond, resulting in a 6-4-photoproduct (<6-4 > PP) [11].

Solar UV can also cause DNA damage by an indirect method, through the formation of reactive oxygen species that attack DNA, particularly the guanine base. This oxidation reaction most often results in 8-oxo-guanosine (8oGua), but even after UVA exposure, CPDs are much more common than 8oGua [12]. Oxidation of DNA can also result in single-stranded breaks, but under physiological conditions, these are very difficult to detect. When single-stranded breaks are found after UV irradiation, they are almost all caused by DNA repair enzymes cutting the DNA in an intermediate step in repair.

Recently, a new pathway has been described wherein fragments of melanin are excited by UV-induced reactive oxygen and nitrogen species and then transfer the energy to DNA to form CPDs even in the dark [13].

Air Pollution Damage to DNA

Pollutants carried in the air are becoming a serious source of DNA damage in urban environments. Carcinogens in tobacco smoke attach an alkyl group to DNA. The most prevalent are at the 7-position of guanine (N7-alklylGua) and to the phosphates of the DNA backbone, but a much less common form of damage, alkylation of the 6-position of guanine (O6-alkylGua) is the most mutagenic and hence the most dangerous. Polyaromatic hydrocarbons coating the surface of air pollutants, particularly 2.5 μm particulates (PM2.5) , are becoming a significant source of 8oGua [14]. Ground-level ozone is also capable of damaging the DNA of keratinocytes [15].

Mechanisms of DNA Repair

DNA is the rare biomolecule that is not discarded when it is damaged, but rather is repaired. Human cells have developed two fundamental repair strategies to restore DNA to its native sequence and conformation.

Nucleotide Excision Repair

More than 20 different proteins participate in this multistep process, and many of these proteins also participate in RNA transcription and/or DNA synthesis. In a typical day, a cell may have to repair 10,000 damaged bases and after sun exposure each cell of the skin may have to remove 100,000 lesions! This process consumes cellular stores of nicotinamide adenine dinucleotide (NAD) , which are used to tag sites of single-stranded breaks and other damages. The depletion of NAD can endanger cell energy reserves, so niacin and niacinamide, members of the vitamin B family and precursors of NAD, are necessary to replenish the NAD reservoir.

Major damage to DNA, such as CPDs or <6-4 > PPs, interferes with its coding ability and must be repaired in order for the nucleotide sequence to function. Each of these is removed in a patch of about 30 DNA nucleotides by a process termed nucleotide excision repair (NER) [16]. A dozen or more proteins may cooperate to complete NER. One subset of these proteins recognizes CPDs throughout the genome because they distort the regular turns of the DNA helix, and they initiate global genomic repair (GGR). However, an additional set of proteins are especially responsive to RNA transcription forks which are stalled at sites of CPDs in the coding sequence, and they are able to more quickly mobilize the NER machinery to these regions of DNA vital to cell function to initiate transcription-coupled repair (TCR).

Once these recognition proteins bind to the site of DNA damage, they recruit additional enzymes that unwind the DNA, make a single-stranded break on either side of the CPD, and release the 30-nucleotide piece of DNA. The single-strand gap is then filled in by DNA polymerases using the opposite strand of the DNA as a template. Each cell has several varieties of DNA polymerases and most of them copy DNA very accurately. However, a few types are much more error prone and when they are called into service, they introduce mutations by incorporating incorrect bases into the patch [17].

NER of CPDs is not a very efficient process. After UV exposure that produces a sunburn in human skin, it takes about 15 h to remove 50 % of the CPD and 5 h to remove 50 % of the <6-4 > PPs [18]. This is due to the fact that <6-4 > PPs are less frequent, and they so greatly distort DNA that they are easier for the NER proteins to locate and excise.

Base Excision Repair

Damage to single bases such as 8oGua distorts DNA much less and is repaired by a second pathway termed base excision repair (BER) [16]. Here a DNA repair enzyme termed an oxoguanine glycosylase-1 (OGG1) specifically recognizes 8oGua and releases it from the DNA backbone, leaving a vacant (abasic) site. A second enzyme recognizes this baseless site and makes a single-stranded break. A few bases on either side of the break are removed, and the short patch is again resynthesized using the opposite strand as a template. This is a speedy process, and half of the 8oGua introduced by solar UV are repaired in about 2 h [19].

In human cells, CPDs are not repaired by BER because there is no glycosylase to recognize them. However, the bacteriophage enzyme T4 endonuclease V recognizes CPDs and clips one side of the CPD from the DNA, initiating BER. Amazingly, when delivered into human cells, this enzyme functions quite well to initiate repair of CPDs by BER [20].


An additional pathway of DNA repair is used by plants, fish, reptiles, and amphibians, but it is not present in humans or other mammals. This repair is accomplished by the enzyme photolyase by directly reversing CPD. It captures long-wavelength UV and visible light and uses the energy to split the bonds that bind together the pyrimidine bases in a CPD [21]. This restores the DNA to normal without producing a single-stranded break or removing any DNA. Once again, while human cells have no photolyase enzymes, when these enzymes are introduced into human cells, they function quite well in repairing CPDs [22].

Diseases of DNA Repair

Much has been learned by studying rare genetic diseases with defects in DNA repair and other diseases in which skin cancer rates are elevated. This has not only clarified the function of many of the DNA repair proteins but has also revealed that many DNA repair proteins have multiple functions in the cell.

Xeroderma Pigmentosum, Trichothiodystrophy, Cockayne Syndrome

Xeroderma pigmentosum (XP) is characterized by mild to extreme photosensitivity, often with areas of hypo- and hyperpigmentation, an increased risk of skin cancer, and a shortened life expectancy [23]. There are seven complementation groups of XP (A-G), corresponding to defects in one of the seven genes that code for proteins involved in NER, and a variant group with a defect in repair synthesis. Stringent photoprotection from an early age can greatly reduce actinic damage, but does not prevent neurological defects that are a hallmark of some of the complementation groups. This may be because some of these genes are also involved in non-DNA repair gene transcription.

Trichothiodystrophy (TTD) patients have a defect in the same gene as XP-D patients, but at different locations within the gene, so they manifest photosensitivity, stunted growth, and brittle hair, but not an increase in skin cancer [23]. This highlights that subtle differences in a DNA repair protein can produce drastic differences in human development and morphology. Patients with Cockayne Syndrome (CS) have mutations in one of the two genes that code for proteins controlling TCR, and they also have growth and developmental abnormalities, but surprisingly little increased risk of skin cancer [23].

Solid Organ Transplant Patients

Organ transplant patients have an elevated rate of skin cancer on sun-exposed skin during the period in which they are on immunosuppressive therapy [24]. There is no doubt that suppression of the immune system plays a significant role in allowing nascent skin cancers to grow out. However, there is increasing evidence that these drugs also impair DNA repair in the skin [25]. The two most widely used drugs, CsA and tacrolimus, target the phosphatase calcineurin. Calcineurin dephosphorylation of the nuclear transcription factor NFAT allows NFAT to localize in the nucleus, where it is a key activator of transcription of several immunoregulatory genes. Immobilization of calcineurin sequesters NFAT in the cytoplasm and shuts down transcription of these genes. Other transcription factors, such as TFHII, are vital to the preferential repair of DNA by targeting the repair machinery to sites of stalled transcription complexes. NFAT may also participate in recovery from transcription blocks. Switching immunosuppressors to those that do not target calcineurin reduces rates of skin cancer [26].

DNA Repair Gene Polymorphisms

The genes implicated in DNA repair deficiency genetic diseases code for proteins that participate not only in DNA repair but in other routine developmental programs and cell functions. The general population carries many forms of these genes with other, less serious, mutations and these forms are called genetic polymorphisms. While some of these polymorphisms are innocuous, some gene forms increase the risk of cancer, including skin cancer [27]. A growing body of evidence suggests that polymorphisms in base excision repair genes contribute to diseases of aging [28].

One such DNA repair gene polymorphism is in the OGG1 gene coding for the glycosylase that releases 8oGua from DNA. The OGG1 polymorphism S326C has been associated with an increased risk of several types of cancer [29]. However, three separate in vitro biochemical studies of the activity of the protein produced by the variant gene failed to identify any deficit in activity or reduced DNA repair of oxidatively damaged DNA [30, 31, 32]. The S326C variant polymorphism in the OGG1 gene is linked to increased risk of cancers such as prostate cancer, but the protein produced by the variant gene does not have any obvious biochemical defects. The variant polymorphic genotype, however, is the most sensitive to cell killing by cytotoxic agents, and the heterozygous genotype was most resistant [33]. The delivery of exogenous OGG1 enzyme to cells increased repair of 8-oxoguanine in the homozygous variants [19]. Thus, subtle changes in DNA repair genes may alter their activity in cells and increase susceptibility to endogenous and exogenous damage.

Prevention of DNA Damage


The first line of defense against DNA damage is the pigment deposited by melanocytes at the surface of the skin. Melanocytes are pigment-producing cells that are found in the basal layer of the epidermis and disperse melanosomes, containing melanin, among the surrounding keratinocytes. These melanosomes encapsulate two main classes of pigment found in the human skin: eumelanin, which is brown or black, and pheomelanin, which is reddish brown. The relative amounts of these two pigments, and the size and density of the melanosomes, largely determine the differences in skin color among humans.

The constitutive pigment that is associated with racial groups is deposited by melanocytes above the nuclei of keratinocytes, thereby shielding them from UV. Skin color has an enormous effect on the risk of skin cancer because this constitutive melanin absorbs and reflects a broad spectrum of UVR. Thus, UV exposure to dark skin produces less DNA damage than in light skin. The induced pigmentation in tanned skin, however, is significantly dispersed as pigment granules, rather than capping nuclei. The result is that tanned skin is much less protective against DNA damage than the equivalent in constitutive color.

As noted previously, new research suggests that fragments of melanin, particularly red pheomelanin, can actually produce DNA damage itself by catalyzing the formation of cyclobutane pyrimidine dimers even in the absence of light [13]. This may well counterbalance the protective effects of melanin, especially in lightly or red pigmented people.


Sunscreens are an additional defense against DNA damage by reflecting or absorbing UV at the skin surface. The absorbed energy is released from the sunscreen molecules mostly as fluorescence or heat. Sunscreens are either inorganic physical sunscreens that largely reflect light or chemical sunscreens that mostly absorb light. Some sunscreens are less photostable than others and lose their absorption capacity during UV exposure. Some of the energy absorbed by sunscreen molecules can cause the release ROS , and this is true of both physical and chemical sunscreens. Recent advances in sunscreen development have been designed to reduce or eliminate these possibilities. To date, there is no evidence that ROS released by sunscreens in skin cause significant levels of DNA damage. Of far greater concern is that sunscreens are usually not used properly or in the right amounts, and despite their application, significant DNA damage still results [34].

The most frequently used physical UV filters are the inorganic micropigments, zinc oxide or titanium dioxide, in the range of 10–100 nm in diameter. These micropigments are capable of reflecting a broad spectrum of UV rays in the UVA and UVB region. Major disadvantages of micropigments are that they also reflect visible light, creating the so-called “ghost” effect on skin, and they are difficult to formulate, often resulting in disagreeable preparations in which the micropigments have a strong tendency to agglomerate, which greatly decrease their efficacy.

Chemical UV filters have the capacity to absorb short-wavelength UV photons and to transform them into heat by emitting long-wavelength photons (infrared radiation) which are much less likely to damage DNA. Most chemical filters absorb in a relatively small wavelength range. In general, chemical filters may be divided into molecules which absorb primarily in the UVB region (290–310 nm) and those which primarily absorb in the UVA region (320–400 nm). Only a few efficiently absorb both UVB and UVA photons. Although these are relatively easier to formulate into cosmetically elegant textures, combinations of chemical filters are required in order to meet regulatory standards for sun protection.


A third protection against the formation of DNA damage is antioxidants. Antioxidants absorb ROS and thereby prevent oxidative DNA damage, primarily 8oGua. The natural skin antioxidant system is composed of lipophilic antioxidants such as vitamin E and CoQ10 and hydrophilic antioxidants such as vitamin C and glutathione and the enzymes catalase and superoxide dismutase. An exciting new finding is that the powerful antioxidant ergothioneine and its receptor (OCNT-1) are found in the suprabasal layer of the epidermis, as well as in dermis. This implicates ergothioneine as a new natural component of the human skin antioxidant system.

Antioxidants cooperate to regenerate each other after reacting with ROS. For example, oxidation of vitamin C leads to its fast degradation, but vitamin E can generate oxidized vitamin C. In the same way, vitamin C can regenerate ergothioneine. Complete antioxidant protection requires many types of antioxidants, since ROS can be in the form of singlet oxygen, superoxides, or peroxides, as well as others. They can also be sequestered in the water or lipid compartment of cells. Therefore, the examination of the antioxidant protection system of skin requires consideration of all the antioxidants as a network.

Cellular Effects of DNA Damage

A complex system regulates the cell’s progression through division to insure that only undamaged ones replicate, in order to avoid genetic instability and cancer [35, 36]. As cells approach commitment to DNA synthesis (S phase), proteins encoded by checkpoint genes delay entry if DNA damage is present. DNA protein kinases, such as ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia mutated and Rad3 related), then initiate signaling cascades resulting in DNA damage responses that include activation of the p53 protein. This tumor suppressor plays a central role in whether a cell repairs the damage [16] or is diverted into programmed cell death (apoptosis), cell cycle arrest, or senescence [35]. New insights reveal that the AKT/mTOR pathway opposes the p53-controlled pathways, inhibiting apoptosis and increasing proliferation even in the face of DNA damage [37].

Mitochondrial DNA is damaged largely as a result of oxidative damage secondary to the production of excess ROS by UV or normal metabolism. Sufficient levels of this damage cause release of mitochondrial factors, such as cytochrome C, which binds to the apoptotic protease-activating factor 1 (Apaf-1), resulting in the formation of the apoptosome. This critical event leads to the activation of caspase-9 and the initiation of the mitochondrial apoptotic pathway through caspase-3 activation [38]. Apoptosis is a critical event preventing damaged cells from progressing to malignancy.

One new photoprotection strategy is to selectively target DNA-damaged cells for apoptosis while leaving normal cells unaffected. Oral administration of caffeine or green tea (which often contains high levels of caffeine) in amounts equivalent to three to five cups of coffee per day to UVB-exposed mice increased levels of p53, slowed cell cycling, and increased apoptotic sunburn cells in the epidermis [39]. Human studies confirm that coffee has a modest protective effect against melanoma [40] and basal cell carcinoma [41].

Signal Transduction

These dramatic events that follow DNA damage indicate that DNA is an important sensor of environmental insult and is able to trigger a variety of cell responses. The molecular mechanisms for this sensor-effector mechanism are being unraveled.

The UV-induced cyclobutane pyrimidine dimers and pyrimidine [4, 5, 6] pyrimidone photoproducts cause distortions in the DNA helix and halt RNA polymerase II (RNA-PII) transcription of DNA. Protein kinases that activate their downstream targets via phosphorylation play an important role in signal transduction. A group of protein kinases that interact with DNA (ATR, Chk2, DNA-PK) are implicated in the molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress [42]. ATR (ATM-Rad3-related kinase) is a primary DNA sensor and essential for UV-induced phosphorylation of several G1/S checkpoint proteins. ATR was also shown to bind UVB-damaged DNA, with a resulting increase in its kinase activity, with many proteins as its target [43].

One such target is the RNA-PII itself, where phosphorylation represses further transcription initiation. This stalled RNA polymerase II leads to recruitment of the nucleotide excision repair complex. Another target of ATR is p53. Following phosphorylation, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Next, a conformational change forces p53 to take on an active role as a transcriptional regulator in these stressed cells. p53 is able to transactivate a plethora of genes with an active role in cell cycle arrest, global genomic DNA repair, apoptosis, and cytokine release.

Systemic Effects of DNA Damage


DNA in skin acts like a sensor for UV damage on behalf of both exposed and unexposed cells in distal parts. DNA damage triggers the production and release of cytokines that act on the cell itself, as well as other cells with such cytokine receptors, to activate characteristic UV responses, such as wound healing and immunosuppression [44]. Keratinocytes are the main source of these cytokines. Other epidermal cells, like Langerhans cells (LHC), and melanocytes, together with infiltrating leukocytes, are also active contributors to changed cytokine profile after UV exposure. Keratinocytes are able to secrete a wide variety of pro-inflammatory cytokines upon UV exposure, including interleukins IL-1α, IL-1β, IL-3, IL-6, and IL-8, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage–CSF (GM-CSF), interferon gamma (INF-γ), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF-α), TGF-β, and tumor necrosis factor-α (TNFα) [45, 46, 47].

Cytokines such as IL-1 and TNFα then induce a cascade of other cytokines that can activate collagen-degrading enzymes, suppress the immune system, dilate blood vessels, and attract inflammatory T cells [48]. In this way, cells with DNA photodamage, even if they are destined to die, have profound effects on cells in the skin and elsewhere that may not have been UV exposed.

IL-12 plays a curious role in photoprotection. It is an immunostimulatory cytokine that is released by keratinocytes at late times after UV in order to counteract the suppressive effects of IL-10 [49]. Recently, it has also been reported to stimulate the repair of CPDs in the DNA of keratinocytes in a manner yet to be understood [50].


UV-induced immunosuppression is an essential event for skin cancer formation [51]. It is important to note that this is not generalized immunosuppression, but a reduced ability to respond to antigens presented just after exposure. There may be a genetic susceptibility to UV-induced suppression, because skin cancer patients are more easily UV suppressed than cancer-free controls [52]. At lower UV doses, the primary target is the Langerhans cells, which flee the epidermis, and those with DNA damage have impaired antigen-presenting ability [53]. Higher doses produce systemic immunosuppression, mediated by the generation of suppressor T cells, in which non-exposed skin becomes hampered in responding to antigens [51]. In several experimental models, including humans, reducing DNA damage decreases the degree of immunosuppression [54].

Wound Healing and Photoaging

UV-induced DNA damage also triggers a wound-healing response in skin, as it tries to eliminate damaged cells and stimulate cell division to replace them. UVR directly to fibroblasts, as well as signals from damaged keratinocytes, causes the release of metalloproteinase (MMP-1) which selectively degrades large collagen cables [55]. Soluble factors released by keratinocytes, including IL-1, IL-6, and TNFα, are principle actors in this paracrine effect [56]. DNA damage is directly related to the release of soluble mediators since enhanced repair of keratinocyte DNA reduced the release of the mediators and lowered the release of MMP-1 by unirradiated fibroblasts [57].

As part of this response, MMP-2 and MMP-9, which are responsible for digesting small collagen fragments, are downregulated by UVR. This results in the accumulation of collagen fragments, which severs the anchorage of fibroblasts, inhibits their ability to produce new collagen, and degrades the dermal elastic fiber network [58]. This is followed by hyperproliferation among keratinocytes, and together these responses are designed to fill in sites of skin wounds.

Repeated rounds of this type of imperfect wound healing produce many of the microscopic hallmarks of photoaged skin, including a corresponding decrease in the biophysical properties of the skin [59], reflected in a loss of both skin strength and elasticity, flattening of the rete ridges, and the appearance of wrinkles and skin folds. Additionally, there are degradative vascular changes in the dermis resulting in telangiectasia and decreases in the capillary network and in skin blood flow [60]. These small changes accumulate after repeated rounds of DNA damage to form what is readily recognized as aged skin.

These connections, from DNA damage to stalled transcription complexes, resulting in kinase cascades activating metalloproteinases which degrade skin collagen, explain why photoaging is a product of unrepaired DNA lesions. It is likely that other sources of DNA damage, such as tobacco smoke and air pollution, induce similar cascades resulting in premature skin aging.

Mutations and Skin Cancer


Most of the solar UV-induced DNA damage distorts the double helix. In attempting to replicate past CPD lesions, the cell often makes the same mistake of misincorporating two consecutive bases, resulting in mutations characteristic of UV damage [4]. In many cases, these mutations have no effect on the cell, but if they occur at critical locations in tumor suppressor genes, they abrogate apoptosis and initiate the process of carcinogenesis. These UV “signature” mutations are often found in mutated p53 genes, a key tumor suppressor gene, in human squamous cell carcinoma and basal cell carcinoma [4]. This is the key link between UV exposure and skin cancer and directly implicates CPDs in carcinogenesis. These p53 signature mutations are also frequently found in precancerous actinic keratosis, suggesting that these mutations are an early step in the process of forming squamous cell carcinomas and that later steps, such as additional gene mutations and immunosuppression, determine if a cell goes on to malignancy.

The situation is less clear in melanoma. There appears to be many different tumor suppressor genes that can be mutated in melanoma, and the frequency of signature mutations is not as common as in squamous cell carcinoma [61].

Mitochondria generate energy for the cell, and they contain DNA that encodes many of the crucial proteins in the energy production machinery. This DNA is also subject to mutations, and mitochondria develop a peculiar type of mutation called the common deletion, in which a particular 477 base pair section of the DNA is deleted. The frequency of the common deletion in the mitochondria of human skin cells does not correlate with chronological age, but rather with sun exposure and photoaging [62]. This implies that solar UV is responsible for the formation of the common deletion, and its contribution to the signs of photoaging is an active area of research.

Prevention of Skin Cancer with DNA Repair Enzymes

The inevitable consequence of the accumulation of DNA damage over a lifetime is an increased incidence of mutations and an elevated risk of skin cancer. The primary strategy for reducing this risk is the attenuation of the UV dose striking the skin, by sun avoidance, pigmentation, and sunscreens. Antioxidants have become a part of the defense by scavenging ROS before they can oxidize DNA. The next step in intervention is the enhanced repair of DNA damage before it can fix as a mutation and increase the probability of malignant transformation.

Over the past 40 years, the field of DNA repair has identified many enzymes that recognize and initiate removal of DNA damage, either by nucleotide excision repair, base excision repair, or direct reversal. The use of some of these enzyme activities for photoprotection became practical with the development of liposomes specifically engineered for delivery into skin [63].

The small protein T4 endonuclease V from bacteriophage recognizes the major form of DNA damage produced by UVB, which is the cyclobutane pyrimidine dimer (CPD). Liposomal delivery of T4 endonuclease V to UV-exposed human skin increased repair from 10 % of CPD to 18 % over 6 h but dramatically reduced or eliminated the release of cytokines such as IL-10 and TNFα [64]. In a randomized clinical study of the effects of the daily use of this liposomal T4 endonuclease V in XP patients, the rate of premalignant actinic keratosis and basal cell carcinoma was reduced by 68 % and 30 %, respectively, compared to the placebo control [65].

Associations with Aging Signs

Sun exposure is the greatest and best understood contributor to skin aging. However, two other external sources of DNA damage are responsible for accelerated skin aging. Cigarette smokers look old for their age, and they have elevated levels of MMP-1 in their skin [66]. More recently, the degree of air pollution has been positively correlated with signs of skin aging, such as wrinkles and pigment spots [67]. Air pollution particles coated with polyaromatic hydrocarbons are particularly dangerous because they can also compromise the barrier function of skin [68] allowing deeper penetration of DNA-damaging compounds.


During a lifetime, skin is exposed to chemical challenges generated by its own metabolism as well as the environment, particularly solar UV. There are a variety of defenses, such as skin color, sunscreens, and antioxidants, to counteract these. Inevitably, however, cells sustain damage.

DNA serves the cell not only as the master controlled of cell function, and the storehouse of heredity information, but also as a sensor of damage and consequently a sentinel for danger to the cell and the organism. It is able to convert the distortion caused by altered nucleic acid bases into signals that arrest and redirect its own cell machinery. It also converts that distortion into notification of adjoining cells, whether damaged or not, that significant lesions have occurred. The purpose of these signals is to evoke repair and healing responses.

DNA is a unique macromolecule in carrying with it the toolkit for its own repair. DNA repair is focused at the site of actively transcribed DNA by a complex of enzymes, some of which are specifically adapted to recognize modified DNA and some borrowed from the transcription machinery itself. The repair may have the task of repairing hundreds of thousands of lesions daily, and while it is an efficient process, it is not perfect. The resulting mutations in the DNA sequence are the necessary components for the development of skin cancer.

Skin aging, therefore, can be viewed as the accumulation of imperfections from repeated rounds of DNA damage and repair, as well as rounds of wounding and healing. Skin cancer is just one manifestation of these cycles. Viewed in this way, it is likely that properly conceived efforts to alleviate skin aging will also have the benefit of reducing rates of skin cancer. Since over long periods of time, people are more motivated by improving their physical appearance than lowering their perceived risk of disease, the most successful anticancer efforts will arrive as treatments for skin aging.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.The Estee Lauder Companies, Inc.MelvilleUSA

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