UV-Induced Mechanisms of Melanomagenesis

Introduction

Melanoma is by far the deadliest form of skin cancer. Although it only makes up about 1% of skin cancers, it is responsible for 80% of skin cancer deaths. Despite this, less than 40% of Americans report practicing adequate sun protection (Saginala Et al. 2021). This paper will assess the current understanding of how UV light causes melanoma and what forms of protection are the most effective.

 Cancer is a group of diseases characterized by the loss of cell cycle regulation. Specific mutations disrupt this regulation by inhibiting apoptosis (programmed cell death) or promoting excessive cell proliferation. When cell division and DNA repair pathways become  unregulated due to damaged genes, the resulting defective cells can invade surrounding healthy tissues, disrupting normal function as they divide uncontrollably. Melanoma is a type of skin cancer that originates from melanocytes, the cells responsible for producing melanin. This pigment gives skin its color and helps protect it from UV radiation. Malignancy occurs when these melanocytes begin to invade surrounding tissues.

The most common cause of melanoma is exposure to Ultraviolet Radiation (UVR). UVR is a spectrum of light that includes wavelengths from 200-400 nanometers (nm). UVR can be broken up into three wavelengths: UVC (200-280nm), UVB (280-320nm), and UVA (320-400nm) (Brozyna Et al. 2007). UVC is mostly absorbed by ozone in the upper atmosphere before reaching the surface. UVA and UVB, on the other hand, both easily pass through the atmosphere and interact with the skin, damaging DNA and causing mutations that may lead to melanoma.

1. Risk Factors

Most of the risk associated with developing melanoma is directly related to the amount of UVR melanocytes are exposed to and their sensitivity to it. Normally, melanocytes protect our skin from the genotoxic effects of UVR by secreting melanin into surrounding skin cells and the extracellular matrix. Melanin protects the DNA by absorbing UVR before it can reach the cell's nucleus. Increased secretion of melanin results in darker skin complexion and tanning; when we are often exposed to the sun, the body acclimates by developing a tan. This is the body’s response to UVR damage to melanocytes and results in greater excretion of melanin. Individuals with a darker complexion naturally produce more melanin, which results in greater protection from UVR than those with a fairer complexion. Consequently, one of the primary risk factors for the development of melanoma is fair skin complexion. Because individuals with a fairer  complexion have less melanin proteins in their skin, they are at higher risk of developing melanoma due to the increase in DNA damage incidence in melanocytes. 

Sunburns are the body's response to UV-induced DNA damage, leading to the programmed death (apoptosis) of affected skin cells. This triggers inflammation, which appears as redness, swelling, and irritation. On a cellular level, nearby blood vessels dilate and become more permeable, allowing immune cells to enter the tissue and remove dead or damaged cells. A significant risk factor for melanoma is the number of sunburns experienced during youth. In “Melanoma Risk Factors and Prevention,” Dzwierzynski found that individuals who experienced 2 to 5 severe sunburns had a 2.4-fold increased relative risk of developing melanoma compared to those with only one sunburn (Dzwierzynski, 2021). Given that the baseline lifetime risk of melanoma in Western populations is approximately 2% (1 in 50), this suggests a substantially elevated risk associated with repeated sunburns.  Individuals lower on the Fitzpatrick scale, which measures complexion and the ability to tan, are more likely to experience sunburns due to their greater UV sensitivity. 

Another group particularly sensitive to UV is patients with the genetic condition Xeroderma Pigmentosum (XP), who often develop skin cancers in sun-exposed areas of the skin. This is a result of a mutation in a UV mutation repair mechanism, which causes a 1000-fold increase in risk for skin cancer compared to other populations (Brozyna 2007). The following section will discuss some of these repair mechanisms as well as the mechanisms for UV-induced melanomagenesis.

2. Mechanisms Of UV Damage

2.1 UVB-Induced Mutations 

UVB radiation causes direct DNA damage by inducing the formation of cyclobutane pyrimidine dimers (CPDs), pyrimidine(6-4)pyrimidone photoproducts (64PPs), and Dewar isomers (derivatives of 64PPs formed through structural rearrangement.) These photoproducts distort the DNA double helix at sites where two pyrimidine bases are adjacent. The pyrimidines, cytosine (C) and thymine (T), are one of two classes of nucleotides. Typically, in a DNA double helix the pyrimidines hydrogen bond to purines, adenine (A) and guanine (G), specifically A-T and C-G. However, under certain energetic conditions, such as when struck by an UV photon, two adjacent pyrimidines, TT, TC, or CC, can spontaneously dimerize, bonding together to form CPDs or 64PPs. Yields of these photoproducts are highest in the UVB range (Brozyna Et al. 2007). 

Melanocytes have a built-in cellular mechanism for repairing such damage called Nucleotide Excision Repair (NER). In NER, DNA damage is recognized by specialized proteins that detect distortions in the DNA helix, such as those caused by bulky lesions like pyrimidine dimers. Once a lesion is identified, a complex of excision proteins, including endonucleases, makes cuts on both sides of the damaged site. The damaged DNA segment is then removed, creating a single-stranded gap. DNA polymerase synthesizes new DNA using the undamaged complementary strand as a template, and DNA ligase seals the final nick to complete the repair (Sample Et al. 2017). Unfortunately, NER sometimes fails, causing DNA damage such as pyrimidine dimers to remain in the sequence until replication. When the DNA replication machinery encounters CPDs, it must stop to allow DNA Polymerase η to carry out  translesion DNA synthesis (TLS). In this process, the polymerase places down the correct complementary nucleotide base pairs despite damage (Ikehata Et al. 2011). Nonetheless, TLS still can’t stop all mutations. 

Pyrimidine dimers CT and CC contain cytosines, which are very energetically unstable in their dimer form compared to their normal, undamaged form. As a result, the cytosines in CPDs readily undergo a reaction called deamination, in which one of their amine groups is converted into a hydroxyl group, causing a cytosine to uracil conversion. Uracil, an RNA base pair, is like thymine in that it is complementary to adenine. During TLS, the newly formed UT or UU dimers are recognized by DNA Pol η as complementary to adenine rather than guanine. Therefore, when another round of replication occurs, those complementary strands will receive a thymine base pair rather than a cytosine as a result of the deaminated CPDs (Ikehata Et al. 2011). This is the cause of C→T mutation patterns, also known as UVB signature or fingerprint mutations. 

Solar-UV signature mutations occur similarly. When cytosine is adjacent to guanine in the DNA sequence, it is energetically prone to undergo methylation, a chemical modification in which a methyl group (–CH₃) is added to the cytosine base, resulting in the formation of 5-methylcytosine (mC). If these mC are adjacent to another pyridine, they are more likely to form CPDs when struck by UVB. These mCs can also undergo deamination, a chemical reaction that removes an amine group from the base. In unmethylated cytosine, this typically produces uracil, which is easily recognized and repaired. However, the presence of the extra methyl group alters the chemistry of the reaction, converting the base into thymine instead, a normal DNA base that is much harder for the cell to recognize as an error, resulting in a permanent mutation (Ikehata et al., 2011). Nevertheless, due to base pairing rules, upon TLS the result is the same: a C→T mutation pattern that remains in cells that originated from that original mutant. 

The above-mentioned mechanisms for UVB-induced mutations are often cited as the source of mutations that ultimately lead to melanoma. However, the C→T mutations signature to UVB are not the only mutations observed in melanomagenesis.

2.2 UVA-Induced Mutations

UVA Radiation, unlike UVB, is generally more attributed to indirect DNA damage. This is because, while UVA wavelengths are weakly absorbed by DNA, they are mostly absorbed by other small molecules in the cell. Upon 'UVA activation,' these molecules produce reactive oxygen species (ROS) that can oxidize and damage DNA (Brozyna et al., 2007).

Oxidative damage alters the DNA in a number of ways. One target of ROS is guanine, which, through oxidation, gains a hydroxyl (OH) group on the 8 position of its ring to form 8-hydroxyguanine (8OH-G). ROS can also attack free nucleotide molecules, which if used in DNA synthesis, introduce damaged nucleotides to the sequence. One example of an oxidized nucleotide is 8-hydroyguanosine-triphosphate (8OH-dGTP) which will become 8OH-G upon addition through DNA synthesis (Ikehata Et al. 2011). 

8OH-G appears to be the most prevalent form of DNA damage induced by ROS, and is usually repaired by a process similar to NER, known as Base Excision Repair (BER). However, much like in the case of NER and TLS, this repair mechanism can fail, resulting in T→G and G→T transversion mutations. These are sometimes referred to as UVA fingerprint mutations because they indicate a specific mutagenic source or mechanism linked to UVA radiation (Ikehata et al., 2011). Although the mechanisms underlying UVA mutagenesis are less well characterized than those of UVB (Brozyna et al., 2007), oxidative damage and UVA fingerprint mutations are nonetheless significant contributors to the genetic risk factors associated with melanoma.

3. Gene Mutants Responsible for Melanoma 

It is clear that UVR is responsible for many different types of mutations, but the question of how these mutations lead to melanoma still remains. The following section will present a few mutant genes that are correlated with a higher incidence of melanoma due to their roles in regulating cellular function. 

3.1 BRAF Mutation

BRAF is a common mutation found in 60% of melanomas (Dzwierzynski 2021). The BRAF gene is part of the MEK/ERK pathway, which is responsible for regulating cell proliferation and apoptosis. Under normal conditions, the BRAF gene encodes a protein that activates the MEK/ERK pathway in response to external signals, promoting controlled cell proliferation and survival. In contrast, melanoma-associated BRAF mutations produce a constitutively active protein that drives proliferation and prevents apoptosis, key features of cancer cells (Teixidó et al., 2021). It is not clear whether UVR is responsible for BRAF mutations. The most common BRAF mutation, V600E, arises as a result of T→A mutation, which isn't a UVR signature. Oxidative damage has been proposed as a potential mechanism but this is not fully agreed upon (Brozyna Et al. 2007). It is clear that the BRAF mutation increases the risk of developing melanoma; however, it is likely that the BRAF mutant alone is not enough to induce melanomagenesis. 

3.2 P53 Mutation

One important mutant gene that does carry UV signature mutations is the p53 mutation. Sometimes called the “genomic guardian,” the p53 tumor suppressor gene is responsible for regulating many pathways related to the cell cycle, proliferation, and apoptosis. Thus, it is unsurprising that p53 mutations are found in a majority of tumors (Brozyna et al. 2007). p53 mutations are typically associated with later, more aggressive stages of melanoma and a worse prognosis (Saginala et al. 2021). However, it is important to clarify that, while p53 mutations themselves rarely initiate melanoma formation, these mutations facilitate cancer progression by impairing the cell's ability to repair DNA damage, control proliferation, or trigger apoptosis. Consequently, cells harboring p53 mutations have an increased susceptibility to additional genetic alterations, thereby 'priming' them for accelerated tumor progression and increased malignancy once initial carcinogenic events have occurred (Brozyna et al. 2007).

3.3 CDKN2A Mutation

Another important gene for the development of melanoma is CDKN2A, which encodes two proteins: p16(INK4A) and p14(ARF). Both proteins are involved in tumor suppression through cell proliferation control. The first protein, p16(INK4A), is responsible for repressing two other proteins, CDK4 and CDK6, which induce cell proliferation and are activated by the MEK/ERK pathway. The second protein, p14(ARF), has the role of protecting the p53 protein from being broken down (MedlinePlus 2018). Mutations to the CDKN2A result in dysfunction for both proteins and often exhibit UV signatures. 

4. Melanoma Prevention 

Understanding UV melanomagenesis is only the first step in protecting against it. The mechanisms previously mentioned indicate that both UVA and UVB radiation are involved in the mutations that lead to melanoma. Therefore, it is important to protect against both of these. The first method for prevention is simply avoiding UV exposure when possible. In fact, “American Cancer Society (ACS) suggests sun avoidance between 10 am and 4 pm, or if not feasible, the usage of hats, clothing, and broad-spectrum sunscreen with a sun protection factor (SPF) of 30 or higher” (Saginala Et. al 2021). Broad-spectrum sunscreen protects against UV-induced sunburn; however, there is currently limited evidence that sunscreen use prevents melanoma (Dzwierzynski, 2021). Regardless, sunscreens containing the inorganic compounds Titanium Dioxide or Zinc Oxide are likely more effective than other sunscreens. In some studies, organic sunscreens have been shown to absorb into the epidermis, where they may actually increase risk for melanoma through ROS production (Dzwierzynski 2021). Secondary prevention methods seek to identify early-stage melanomas through screening. Self-examination has also been shown to be effective in Australia, a particularly high-risk region due to levels of UV radiation, where “melanoma mortality was reduced by 63% by early melanoma diagnosis through skin self-examination” (Dzwierzynski 2021)

Conclusion 

It is clear that, although we can identify trends in what mutations occur from UV radiation and which gene mutants show up in melanoma, there is no one definitive cause of melanoma, but rather many different factors that contribute to overall risk. No two melanomas are the same, and there are many factors affecting melanomagenesis. Future research should study less common mutations resulting from 64PPs, Dewar isomers, and thymine glycols. Additional investigation of UVA mutagenesis would also be beneficial, as current research disagrees about the exact mechanism of UVA damage. Finally, it would be interesting to research novel forms of melanoma prevention, such as chemoprevention, as they approach prevention differently from more traditional forms.

About the Author: Dimitrios Zannis

Dimitrios Zannis graduated from UC Davis in the spring of 2025 with a B.S. in Biochemistry and Molecular Biology. He is now working at UCSF as a Junior Specialist in the Cho Lab engineering cellular cancer immunotherapies and studying cancer-immune interactions in the context of radiation therapy. As a University Honors Program student, he completed his honors thesis on high-throughput screening strategies for anticancer compounds and has contributed to projects in protein engineering, molecular diagnostics, and drug discovery. This article reflects his deep interest in cancer biology, examining how ultraviolet radiation drives melanoma initiation and progression. He plans to pursue an MD-PhD to develop immunotherapies and advance precision oncology.

Author’s Note

I chose to write this literature review on the mechanisms by which UV radiation can lead to melanoma because I’ve long been fascinated by the molecular underpinnings of carcinogenesis. In this paper, I explore the sequence of biochemical events that begin with UV-induced DNA damage and culminate in the driver mutations that may lead to skin cancer. My goal was to trace the molecular journey from a seemingly simple environmental exposure, UV radiation, to a disease as devastating as melanoma. 

Through this review, I hope to shed light on the elegance and complexity of our body’s defense systems, which work constantly to repair such damage, and to underscore the importance of protecting ourselves from excessive sun exposure. The intended audience for this paper includes undergraduate students in biology and biochemistry who are curious about the molecular mechanisms behind how environmental factors like carcinogens contribute to cancer development.

References

1.  Brozyna A, Zbytek B, Granese J, Carlson JA, Ross J, Slominski A. 2007. Mechanism of UV-related carcinogenesis and its contribution to nevi/melanoma. Expert Rev Dermatol [Internet]. 2(4):451–469. https://doi.org/10.1586/17469872.2.4.451
2. Dzwierzynski WW. 2021. Melanoma risk factors and prevention. Clin Plast Surg [Internet]. 48(4):543–550. https://doi.org/10.1016/j.cps.2021.05.001
3. Ikehata H, Ono T. 2011. The mechanisms of UV mutagenesis. J Radiat Res [Internet]. 52(2):115–125. https://doi.org/10.1269/jrr.10175
4. MedlinePlus. 2018. BRAF gene [Internet]. Bethesda (MD): National Library of Medicine (US). Accessed 2025 Jul 16. https://medlineplus.gov/genetics/gene/braf/
5. MedlinePlus. 2018. CDKN2A gene [Internet]. Bethesda (MD): National Library of Medicine (US). Accessed 2025 Jul 16. https://medlineplus.gov/genetics/gene/cdkn2a/
6. MedlinePlus. 2020. TP53 gene [Internet]. Bethesda (MD): National Library of Medicine (US). Accessed 2025 Jul 16. https://medlineplus.gov/genetics/gene/tp53/
7. Saginala K, Barsouk A, Aluru JS, Rawla P, Barsouk A. 2021. Epidemiology of melanoma. Med Sci (Basel) [Internet]. 9(4):63. https://doi.org/10.3390/medsci9040063
8. Sample A, He YY. 2018. Mechanisms and prevention of UV-induced melanoma. Photodermatol Photoimmunol Photomed [Internet]. 34(1):13–24. https://doi.org/10.1111/phpp.12329
9. Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. 2021. Molecular markers and targets in melanoma. Cells [Internet]. 10(9):2320. https://doi.org/10.3390/cells10092320