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Pyrimidine dimer

A pyrimidine dimer is a type of DNA lesion consisting of covalent intrastrand cross-links formed between adjacent pyrimidine bases—thymine (T) or cytosine (C)—primarily due to exposure to ultraviolet (UV) radiation from sunlight. These dimers distort the DNA double helix structure, thereby blocking essential cellular processes such as DNA replication and transcription, which can lead to cell death, mutations, or oncogenic transformations if unrepaired. The most prevalent forms include cyclobutane pyrimidine dimers (CPDs), where a cyclobutane ring links the 5,6 double bonds of neighboring pyrimidines (e.g., T-T, T-C, or C-C), and (6-4) photoproducts, which involve a bond between the carbon 6 of one pyrimidine and carbon 4 of the adjacent one. Pyrimidine dimers arise mainly from the direct absorption of UVB (280–315 nm) and UVA (315–400 nm) wavelengths by DNA, with CPDs being the predominant lesion in human skin exposed to solar UV. Their formation is a key mechanism underlying UV-induced skin damage, including immunosuppression, premature aging, and cancers such as melanoma and non-melanoma skin carcinomas, as unrepaired dimers can cause characteristic C-to-T transition mutations at dipyrimidine sites. In evolutionary terms, these lesions represent one of the most ancient and widespread genotoxic threats, prompting the development of dedicated DNA repair pathways across organisms. Cells counteract pyrimidine dimers through multiple repair mechanisms, with serving as the primary pathway in mammals, where proteins like XPC-hHR23B recognize and excise the damaged segment. In many , , and fungi, photoreactivation employs UV-specific DNA photolyases that use blue/UV-A light to directly reverse CPDs via electron transfer, splitting the cyclobutane ring without excising DNA. Additionally, (BER) and specialized glycosylases, such as T4 endonuclease V from T4, can target and remove these lesions, underscoring the critical role of repair efficiency in preventing UV-associated pathologies.

Introduction and Formation

Definition and Chemical Structure

Pyrimidine dimers are intrastrand covalent linkages that form between two adjacent pyrimidine bases—thymine (T) or cytosine (C)—within a DNA strand, resulting in a structural distortion of the DNA double helix that disrupts normal base pairing and helical geometry. These lesions primarily arise from ultraviolet (UV) radiation exposure, which induces photochemical reactions between the bases. The chemical structure of pyrimidine dimers involves the formation of bonds between the C5 and C6 atoms of neighboring pyrimidine residues, saturating the C5=C6 double bonds and creating a non-planar configuration that prevents standard Watson-Crick hydrogen bonding. This linkage occurs within the same DNA strand, leading to a localized kink or bend in the helix backbone. Common dimer types include thymine-thymine (TT), thymine-cytosine (TC), cytosine-thymine (CT), and cytosine-cytosine (CC), with TT dimers being the most frequently observed due to higher reactivity at these sites. Unlike purines (adenine and guanine), which lack the equivalent C5=C6 double bond configuration conducive to such cycloaddition reactions, only pyrimidines are prone to forming these dimers under UV exposure; purines may experience indirect damage from adjacent pyrimidines but do not dimerize directly. This specificity arises from the structural features of pyrimidine rings, enabling the [2+2] photocycloaddition across their 5,6-double bonds.

Mechanism of Formation by UV Radiation

Pyrimidine bases in DNA, such as thymine and cytosine, primarily absorb ultraviolet B (UVB, 280–315 nm) and ultraviolet C (UVC, 100–280 nm) radiation, exciting their π-electrons from the ground state to a reactive singlet or triplet excited state. This photoexcitation promotes the bases to undergo photochemical reactions, most notably a [2+2] cycloaddition between the C5=C6 double bonds of adjacent pyrimidines on the same DNA strand, resulting in the formation of covalent dimers. The process begins with the absorption of a UV photon by one pyrimidine base, elevating it to an excited state where its electron configuration becomes conducive to bond formation. In the subsequent step, the excited base approaches the neighboring pyrimidine, enabling the concerted or stepwise [2+2] cycloaddition across their C5–C6 bonds, which saturates the double bonds and creates a cyclobutane ring linking the two bases. This reaction occurs intramolecularly within the DNA helix, typically between adjacent bases, and is favored in the anti conformation of the DNA strand. Although less efficient than UVB or UVC, ultraviolet A (UVA, 315–400 nm) radiation also contributes to pyrimidine dimer formation, primarily through indirect mechanisms involving oxidative stress from reactive oxygen species (ROS), such as singlet oxygen generated via photosensitization. Recent studies in 2025 have confirmed that UVA can induce cyclobutane pyrimidine dimers directly in cellular DNA via photochemical absorption, in addition to indirect contributions from ROS-mediated processes, emphasizing its role in skin damage beyond traditional UVB effects. Several factors modulate the efficiency of dimer formation. DNA sequence context significantly influences reactivity, with thymine-thymine (TT) dipyrimidines exhibiting the highest susceptibility due to optimal orbital overlap, followed by , , and sites in decreasing order. Hydration levels affect the reaction, as reduced enhances base stacking and proximity, increasing dimer yields compared to fully hydrated environments. Additionally, structure plays a key role, with positioning periodically modulating UV accessibility—damage is reduced at sites where the DNA is tightly wrapped around histones, exhibiting a ~10.3-base periodicity in formation rates. The yield of pyrimidine dimers is directly proportional to the UV dose, reflecting the photochemical nature of the process. For instance, exposure to 10 J/m² of UVB radiation typically generates approximately 3,000 dimers per mammalian cell, establishing a scale where even low environmental doses can accumulate significant lesions across the genome.

Types of Pyrimidine Dimers

Cyclobutane Pyrimidine Dimers (CPDs)

Cyclobutane pyrimidine dimers (CPDs) form through a [2+2] cycloaddition reaction between the C5-C6 double bonds of two adjacent pyrimidine bases in DNA, resulting in a saturated four-membered cyclobutane ring that covalently links the bases. This linkage distorts the DNA helix, causing an approximately 30° bend toward the major groove and about 9° of unwinding. The most common CPD involves two thymine bases (TT), followed in frequency by TC, CT, and CC dimers. CPDs were first identified in 1960 by Rob Beukers and Wouter Berends, who isolated and characterized the irradiation product of thymine in frozen aqueous solutions exposed to ultraviolet light, demonstrating the formation of a cyclobutane-linked dimer. This discovery laid the foundation for understanding UV-induced DNA damage. Subsequent studies confirmed that CPDs arise in vivo from adjacent pyrimidines in cellular DNA upon UV exposure. CPDs represent the predominant type of UV-induced dimer, accounting for 70-80% of such lesions in DNA. Their high prevalence stems from the susceptibility of pyrimidine 5-6 bonds to UV absorption, with sites being particularly prone due to structural alignment in the B-form . In biological contexts, such as , CPDs have a repair of approximately 33 hours via , allowing time for potential mutagenic effects if unrepaired. Detection of CPDs relies on sensitive methods that exploit their and antigenic properties. Enzyme-linked immunosorbent assay () using monoclonal antibodies specific to CPDs enables quantification in cellular extracts or tissue samples with high throughput. Chromatographic techniques, such as (HPLC), separate CPDs after enzymatic digestion, while liquid chromatography-mass spectrometry (LC-MS) provides precise identification and quantification by analyzing mass-to-charge ratios of dimer fragments.

(6-4) Photoproducts

(6-4) photoproducts, also known as pyrimidine (6-4) pyrimidone photoproducts, are a class of DNA lesions formed by ultraviolet (UV) radiation, distinct from cyclobutane pyrimidine dimers in their chemical linkage and structural impact. These lesions arise from adjacent pyrimidine bases, primarily thymine or cytosine, through a photochemical reaction that establishes a covalent bond between the C6 atom of the 5' pyrimidine and the C4 atom of the 3' pyrimidine, converting the 3' base into a planar pyrimidone ring. The 5' base adopts a half-chair conformation, while the bases orient nearly perpendicular to each other (approximately 99° angle), disrupting standard Watson-Crick base pairing. In the DNA duplex, the 5' base often retains partial hydrogen bonding via its N3 and O2 atoms, but the 3' pyrimidone typically forms no such bonds, leading to severe helical distortion including a bend of about 44° in the DNA backbone. Unlike the direct [2+2] forming cyclobutane dimers, (6-4) photoproducts result from UV excitation (primarily UVB wavelengths around 260-280 nm) via an intermediate, involving hydroxyl transfer to the position of the 3' base and yielding a unique . They account for 20-30% of total UV-induced pyrimidine dimers, making them less prevalent than cyclobutane dimers (70-80%), and show a site preference for TC and dinucleotides over sequences. These photoproducts exhibit lower stability compared to cyclobutane dimers, undergoing photoisomerization to Dewar valence isomers upon additional UV exposure (e.g., at 313 nm), which involves ring closure on the pyrimidone moiety. Detection typically employs monoclonal antibodies like 64M-5 for immunohistochemical or ELISA assays, or high-performance liquid chromatography (HPLC) with fluorescence or mass spectrometry for quantitative analysis in DNA extracts. Their relative instability facilitates faster repair by nucleotide excision repair pathways relative to cyclobutane dimers. Recent studies from 2024-2025 highlight UVA's role in modulating (6-4) photoproducts through photosensitization, where existing lesions absorb UVA to trigger intramolecular reactions like electrocyclization to Dewar isomers, potentially exacerbating oxidative damage via reactive oxygen species generation.

Biological and Cellular Effects

Mutagenesis and Mutation Signatures

Pyrimidine dimers, formed primarily by ultraviolet (UV) radiation, obstruct high-fidelity replicative DNA polymerases during DNA replication, causing replication fork stalling and the formation of single-stranded gaps opposite the lesion. To resume replication, cells utilize translesion synthesis (TLS), an error-prone process involving specialized low-fidelity DNA polymerases. DNA polymerase η (Pol η) serves as the primary TLS polymerase for cyclobutane pyrimidine dimers (CPDs), accurately inserting two adenine nucleotides opposite thymine-thymine (TT) dimers, which is largely error-free for this specific lesion but can lead to mutations at cytosine-containing sites due to cytosine deamination within the dimer. In contrast, DNA polymerase ζ (Pol ζ) often participates in the extension step after nucleotide insertion, contributing to error-prone bypass and increased mutagenesis across various dimer types. The mutational consequences of unrepaired pyrimidine dimers manifest as characteristic UV signature mutations, predominantly C→T transitions occurring at dipyrimidine sequences (e.g., converting TCC to at a 5'-TC-3' site). Tandem CC→TT mutations, where both cytosines in a CC dinucleotide mutate to thymines, represent a hallmark of UV exposure and are directly linked to deamination of cytosine within CPDs followed by erroneous adenine insertion. These signatures arise because the distorted dimer structure promotes misincorporation, particularly when cytosine deaminates to uracil, which pairs with during TLS. Genomic analyses of UV-induced cancers consistently reveal that over 60% of point are C→T transitions at or dipyrimidine sites, underscoring the role of pyrimidine dimers in . Recent studies from 2020 to 2025, including whole-genome sequencing of melanomas, have confirmed this pattern, with UV-associated melanomas showing enriched C→T at CPD hotspots and recurrent driver alterations fitting the signature, such as in BRAF and NRAS genes. Sequence context significantly influences , with 5'-TC-3' motifs emerging as hotspots due to higher dimer formation and slower repair rates compared to TT sites. Unrepaired dimers can elevate frequencies by 10- to 15-fold or more, depending on the cellular repair proficiency and UV dose, amplifying the of oncogenic transformations.

Impact on and Transcription

Pyrimidine dimers, particularly cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts, physically distort the DNA helix, obstructing the progression of DNA polymerases during replication. High-fidelity replicative polymerases, such as DNA polymerase δ and ε, are unable to accurately synthesize past these lesions, leading to replication fork stalling when a dimer is encountered on the template strand. In vitro studies demonstrate that even a single CPD on the leading strand template causes transient arrest of the replication fork, as evidenced by two-dimensional gel electrophoresis showing halted bubble arc progression in plasmid replication assays using human cell extracts. To resume replication, cells recruit translesion synthesis (TLS) polymerases, such as polymerase η, which enable low-fidelity bypass of the dimer but at the risk of introducing errors. (6-4) photoproducts are more helix-distorting than CPDs, often causing stronger obstruction and triggering more immediate replication stress responses despite their lower abundance. These lesions similarly impede transcription by stalling (Pol II) at the site of damage, particularly when the dimer is located on the transcribed strand. UV-induced CPDs halt Pol II elongation, forming stable ternary complexes that block nucleotide incorporation opposite the lesion, thereby reducing overall in exposed cells. This stalling activates p53-dependent signaling pathways, including the accumulation of p53-binding protein 1 (53BP1) foci and enhanced expression of damage-responsive genes, which help coordinate cellular recovery but can lead to transient suppression of transcription. In UV-exposed human fibroblasts, Pol II arrest at dimers correlates with decreased mRNA levels for key regulatory genes, underscoring the acute disruption to cellular . Prolonged replication stalling due to unresolved dimers activates intra-S-phase checkpoints, delaying S-phase progression and preventing mitotic entry until is addressed, as CPD directly correlates with checkpoint in irradiated cells. , solar UV exposure induces approximately 100–1,000 CPDs per in epidermal cells, sufficient to cause widespread and contribute to genomic if not repaired. Recent studies highlight age-related vulnerabilities, showing that suberythemal UV doses—common in daily —result in persistent CPD accumulation and slower repair in elderly (ages 55–70), exacerbating replication delays compared to younger individuals. These effects collectively promote or in chronically exposed tissues, amplifying long-term risks without resolving the underlying obstructions.

Repair Mechanisms

Nucleotide Excision Repair (NER)

Nucleotide excision repair (NER) serves as the principal pathway in eukaryotes for eliminating pyrimidine dimers, such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts, formed by (UV) radiation exposure. This ATP-dependent process excises an segment of 24-32 nucleotides containing the , followed by accurate resynthesis using the undamaged strand as a template. The pathway recognizes these lesions primarily through the structural distortions they induce in the DNA helix, including kinking and base flipping that disrupt normal base pairing. NER encompasses two distinct subpathways tailored to different genomic contexts: global genome NER (GG-NER) and transcription-coupled NER (TC-NER). GG-NER surveys the entire genome, including non-transcribed regions, to detect and repair damage throughout the DNA. In contrast, TC-NER specifically targets the transcribed strands of active genes, where stalled serves as the initial signal for repair initiation, ensuring rapid recovery of essential transcriptional processes. The core steps of NER are conserved across both subpathways after initial recognition, though the initiators differ. In GG-NER, the XPC-RAD23B complex binds to the distorted DNA at the lesion site to initiate damage verification. In TC-NER, the CSA and CSB proteins are recruited to the stalled transcription complex to facilitate recognition. Subsequently, the TFIIH complex, containing XPB and XPD helicases, unwinds the DNA duplex around the lesion to create a bubble structure approximately 25-30 base pairs in size. Verification and stabilization occur via XPA and replication protein A (RPA), which confirm the presence of the bulky adduct and recruit additional factors. Dual incisions are then executed by the endonucleases XPG on the 3' side and XPF-ERCC1 on the 5' side of the lesion, releasing the damaged oligomer. The single-strand gap is filled through DNA synthesis by polymerases δ and ε, in conjunction with PCNA and RFC, and sealed by DNA ligase 1 or the XRCC1-LIG3 complex. In normal human cells, NER efficiently removes 50-80% of induced pyrimidine dimers within several hours post-UV exposure, with CPDs typically exhibiting slower repair kinetics compared to (6-4) photoproducts. Defects in NER components underlie disorders like (XP), where impaired repair leads to persistent dimer accumulation and a greater than 1000-fold elevated risk of UV-induced . Recent investigations (2024-2025) indicate that CPDs generated by radiation, which penetrate deeper into tissues, are repaired more slowly by NER due to oxidative interference from that impair repair protein function and overall pathway efficiency.

Photoreactivation and Other Pathways

Photoreactivation, the light-dependent reversal of UV-induced pyrimidine dimers, was first discovered in 1949 by Albert Kelner, who observed recovery in UV-irradiated spores of Streptomyces griseus upon exposure to visible light. The mechanism was elucidated in the early 1960s, revealing it as an enzymatic process involving a photolyase that binds to the damaged DNA and utilizes light energy to restore the original bases. In this repair pathway, specialized photolyase enzymes—either cyclobutane pyrimidine dimer (CPD) photolyase or (6-4) photoproduct photolyase—recognize and bind to the UV-induced lesions in DNA. Activation occurs through absorption of blue light or UV-A wavelengths (300-500 nm), which excites the fully reduced flavin adenine dinucleotide cofactor (FADH⁻) within the enzyme. This excitation facilitates electron transfer from FADH⁻ to the dimer, generating a radical anion that splits the cyclobutane ring or (6-4) linkage, thereby directly reversing the damage without excising nucleotides. The process is highly efficient in organisms such as bacteria (e.g., Escherichia coli), plants, and fish, where it can repair over 80% of induced dimers under optimal light conditions, often approaching or exceeding 90% in E. coli. This mechanism is absent in placental mammals, including humans, due to the evolutionary loss of functional photolyase genes, leaving (NER) as the primary pathway for dimer removal in these organisms. In non-mammalian species, photoreactivation serves as a rapid, energy-efficient complement to other repair systems. Other repair pathways play secondary roles in addressing pyrimidine dimer-related damage. (BER) primarily handles oxidized pyrimidine derivatives, such as glycol, arising from UV exposure or secondary oxidation of dimers, through glycosylase-initiated removal of the altered base. Mismatch repair (MMR) contributes minimally, mainly by suppressing from replication errors opposite unrepaired lesions rather than directly excising dimers. Recent efforts to engineer photoreactivation in human cells, such as through expression of bacterial photolyase, have shown promise in enhancing UV damage reversal in experimental models.

Prevention and Health Implications

Effects of Sunscreens

Topical sunscreens, particularly broad-spectrum formulations that protect against both UVA and UVB radiation, play a crucial role in mitigating pyrimidine dimer formation by absorbing or scattering ultraviolet (UV) light before it reaches DNA in skin cells. Chemical filters such as avobenzone primarily absorb UVA rays, converting them into harmless heat, while physical blockers like zinc oxide reflect and scatter both UVA and UVB wavelengths across the skin surface. With proper application of SPF 30 or higher, these sunscreens can reduce UV penetration by approximately 97%, correlating with 80-95% less formation of cyclobutane pyrimidine dimers (CPDs) and other pyrimidine photoproducts in human epidermis exposed to solar-simulated radiation. Although some chemical UV filters in sunscreens can be absorbed systemically through the skin, leading to potential generation of reactive oxygen species (ROS) upon UV exposure, their overall effect remains net protective due to superior UV blocking compared to the minor ROS contribution. In contrast, physical blockers like zinc oxide exhibit minimal skin penetration, reducing concerns over systemic absorption while providing broad-spectrum coverage without significant ROS production. Studies indicate that even with partial absorption of chemical filters, the reduction in UV-induced DNA damage, including pyrimidine dimers, outweighs any localized oxidative stress. Effective sunscreen use depends on application factors such as achieving even coverage at 2 mg/cm² and reapplying every 2 hours, especially after or sweating, to maintain protection levels. Irregular or sub-optimal application, such as using half the recommended amount, can result in up to 50% breakthrough of UV damage, allowing substantial pyrimidine dimer formation despite labeled . Clinical trials spanning 2001 to 2023 demonstrate that daily use of broad-spectrum sunscreens significantly lowers pyrimidine dimer levels in ; for instance, regular application during recreational exposure reduced urinary and epidermal photoproducts by over 50% compared to unprotected controls. A 2023 real-world study confirmed that SPF 50+ sunscreens prevented detectable increases in dimers in volunteers during summer activities, underscoring the preventive efficacy of consistent use.

Role in UV-Induced Diseases

Pyrimidine dimers, primarily cyclobutane pyrimidine dimers (CPDs), are key initiators of UV-induced skin cancers through their role in , leading to characteristic C→T transition mutations at dipyrimidine sites. These mutations dominate the genomic profiles of non-melanoma skin cancers, including (BCC) and (SCC), where UV-signature alterations are present in the vast majority of cases. In , approximately 65-83% of tumors exhibit this C→T signature attributable to UV exposure and unrepaired dimers, establishing a direct link between dimer persistence and oncogenic transformation. Unrepaired pyrimidine dimers also contribute to non-cancerous UV-induced conditions such as and . In , stalled transcription at dimer sites reduces expression of collagen-encoding genes, causing dermal collagen degradation and characteristic wrinkles and elasticity loss. arises as dimers signal the depletion of Langerhans cells in the , weakening local immune responses and facilitating or tumor escape. Data from 2025 research highlights that aging impairs dimer repair efficiency, with elderly skin showing prolonged persistence of lesions and elevated risk for these conditions due to diminished capacity. Globally, the health burden of -related diseases is substantial, with over 1.5 million new cases estimated annually worldwide as of 2022, predominantly non-melanoma types driven by UV exposure. High-UV regions like experience 2-3 times the incidence rates compared to the world average, reflecting intensified dimer formation from cumulative sun exposure. Individuals with (XP), due to deficiencies, face a >10,000-fold increased risk of , with onset as early as age 8-10 in unprotected cases, as unrepaired dimers accumulate and lead to mutations.

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