How Can Pyrimidine Dimers Lead to Cancer?

Ultraviolet (UV) radiation from the sun damages DNA, increasing the risk of cancer. One major type of UV-induced DNA damage is pyrimidine dimer formation, which disrupts cellular processes and contributes to genomic instability.

Understanding how these dimers interfere with DNA function and how cells repair them is key to explaining their role in cancer development.

Molecular Formation Of Pyrimidine Dimers

UV radiation, particularly UV-B (280–315 nm) and UV-C (100–280 nm), directly damages DNA by inducing pyrimidine dimers. These lesions form when adjacent pyrimidine bases—typically thymine or cytosine—covalently bond after absorbing UV photons. The absorbed energy excites electrons in the pyrimidine rings, leading to cyclobutane pyrimidine dimers (CPDs) and, less frequently, 6-4 photoproducts (6-4 PPs). CPDs create a four-membered cyclobutane ring between two adjacent pyrimidines, while 6-4 PPs involve a covalent bond between the C6 position of one pyrimidine and the C4 position of the neighboring base. Both distort the DNA double helix, disrupting base pairing and structural integrity.

The formation of pyrimidine dimers is influenced by sequence context and chromatin structure. Dipyrimidine sequences, particularly TT, TC, and CC dinucleotides, are highly prone to dimerization, with TT dimers being the most common. Additionally, DNA regions that are more exposed due to chromatin relaxation or transcriptional activity exhibit higher dimer formation rates. Genome-wide sequencing studies confirm that actively transcribed genes and regulatory elements accumulate more UV-induced lesions, emphasizing the role of chromatin accessibility in DNA damage susceptibility.

Once formed, pyrimidine dimers introduce structural distortions that impede normal base pairing and replication. CPDs cause a 7–9° bend in the DNA backbone, while 6-4 PPs induce even greater helical distortion. These changes hinder DNA polymerases, increasing replication errors. If not repaired, these lesions contribute to mutagenesis and genomic instability, particularly in rapidly dividing cells exposed to chronic UV radiation.

Effects On DNA Replication

Pyrimidine dimers obstruct the replication machinery, particularly during S-phase when cells duplicate their genetic material. These lesions stall replication forks, as high-fidelity DNA polymerases δ and ε struggle to incorporate nucleotides opposite the damaged sites.

To bypass these lesions, cells use translesion synthesis (TLS) polymerases, such as polymerase η, ι, and κ, which can accommodate distorted templates. Unlike high-fidelity polymerases, TLS enzymes have more flexible active sites, allowing them to insert nucleotides opposite the dimer. However, this process is error-prone. Polymerase η, for example, frequently inserts adenines opposite thymine dimers, a phenomenon known as the “A-rule,” which increases the risk of mutations.

Beyond single-nucleotide mismatches, persistent pyrimidine dimers can cause severe genomic instability, including double-strand breaks and chromosomal rearrangements. If replication forks collapse due to unrepaired lesions, cells rely on homologous recombination or break-induced replication for genome restoration. These repair pathways, though necessary, are inherently error-prone and can lead to deletions, insertions, or translocations. Genome-wide sequencing of UV-exposed cells reveals a characteristic mutation signature dominated by C→T transitions at dipyrimidine sites—a hallmark of UV-induced mutagenesis commonly observed in skin cancers.

Cellular Repair Pathways

Cells counteract pyrimidine dimers primarily through nucleotide excision repair (NER). This process begins when damage recognition proteins, such as XPC-RAD23B, detect distortions in the DNA helix. The transcription factor TFIIH, along with helicases XPB and XPD, then unwinds the DNA around the lesion. Endonucleases XPF-ERCC1 and XPG excise a short segment containing the dimer, after which DNA polymerase δ or ε synthesizes the missing nucleotides, and DNA ligase seals the strand.

NER efficiency varies across cell types and genomic regions. Actively transcribed genes benefit from transcription-coupled repair (TCR), a sub-pathway of NER. When RNA polymerase stalls at a pyrimidine dimer, Cockayne syndrome proteins CSA and CSB recruit repair factors to rapidly remove the damage, minimizing transcriptional errors. This explains why mutations in TCR-related genes, such as ERCC6 (CSB) and ERCC8 (CSA), lead to neurodegenerative disorders rather than an increased cancer risk, as seen in NER-deficient conditions like xeroderma pigmentosum.

If NER fails or is overwhelmed, cells rely on alternative pathways. Base excision repair (BER) corrects oxidative modifications from prolonged UV exposure, while damage tolerance mechanisms like translesion synthesis (TLS) allow replication to proceed despite lesions—though at the cost of increased mutagenesis. The balance between accurate repair and error-prone bypass determines whether a cell maintains genomic stability or accumulates mutations that drive malignant transformation.

Mechanisms Leading To Tumorigenesis

Mutations from pyrimidine dimer-induced DNA damage create a permissive environment for tumorigenesis by altering genes that regulate cell division and genomic stability. One of the most frequently mutated genes in UV-induced cancers is TP53, a tumor suppressor that governs cell cycle arrest and apoptosis in response to DNA damage. Skin cancer genome analyses reveal a distinct pattern of C→T transitions at dipyrimidine sites within TP53, directly linking these mutations to UV exposure. When TP53 is compromised, damaged cells continue proliferating, increasing the likelihood of additional oncogenic mutations.

Beyond TP53, mutations in the mitogen-activated protein kinase (MAPK) pathway further drive malignant transformation. The BRAF gene, which encodes a kinase involved in cell growth signaling, frequently harbors V600E mutations in melanoma, leading to uncontrolled proliferation. Whole-genome sequencing of melanoma samples shows that UV-induced pyrimidine dimer mutations in BRAF occur early in tumor development, highlighting a direct connection between UV exposure and cancer progression. The interplay between defective DNA repair, disrupted tumor suppressor activity, and hyperactive growth signaling creates a cellular environment primed for malignancy.