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Thymine DimerEdit

Thymine dimers are a fundamental form of DNA damage arising when cells are exposed to ultraviolet (UV) radiation. The most common lesion is a cyclobutane pyrimidine dimer (CPD), formed when two neighboring thymine bases on the same DNA strand become covalently linked. A rarer but more distorting lesion, the 6-4 photoproduct (6-4PP), also results from UV exposure. These lesions distort the DNA double helix, challenging the accuracy of replication and transcription, and they are central to our understanding of how sun exposure can contribute to cancer risk and aging. The study of thymine dimers has driven major advances in the biology of DNA repair and cellular responses to environmental stress, and it remains a cornerstone of photobiology and cancer biology.

Formation and Types

  • CPDs form most readily under UVB and, to a lesser extent, UVA irradiation, with adjacent thymines being the prime substrate. They are the predominant thymine dimer type observed after solar exposure.
  • 6-4 photoproducts are less frequent but typically more distorting to the DNA helix than CPDs, and they can be repaired with different efficiency by repair systems in various organisms.
  • The chemical structures and positional constraints of these lesions influence how easily repair pathways recognize and remove them. For example, CPDs can be more insidious due to their subtler distortion, whereas 6-4PPs tend to be more conspicuous to damage-recognition proteins.

Biological consequences and mutagenesis - Thymine dimers physically block DNA polymerases, which can stall replication and transcription if left unrepaired. This stalling can lead to fork collapse, genome instability, and cell death or senescence in severe cases. - If replication bypass occurs, thymine dimers can introduce mutations, most often at dipyrimidine sites, contributing to mutational spectra observed in UV-related cancers. The exact mutations depend on sequence context and the fidelity of the bypass polymerases involved. - The cellular consequences of thymine dimers depend on the interplay between damage formation, repair efficiency, and the cell’s capacity to tolerate or fix lesions without introducing errors. In multicellular organisms, cumulative unrepaired damage is a major driver of aging and carcinogenesis in tissues frequently exposed to UV light, notably the skin.

Repair mechanisms - Nucleotide excision repair (NER) is the principal repair pathway for thymine dimers in humans and many other organisms. NER detects helical distortions, excises a short single-stranded DNA segment containing the lesion, and fills the gap with new DNA synthesized by DNA polymerases before ligation. - In many bacteria, plants, and some other organisms, photoreactivation can directly reverse CPDs using energy from visible light via the enzyme photolyase. This process bypasses the need for excision and resynthesis and provides a rapid, light-dependent repair option. - In humans, photoreactivation is largely absent or limited, making NER the essential defense against UV-induced thymine dimers. Defects in NER underpin disorders such as Xeroderma pigmentosum, a condition marked by extreme sensitivity to sunlight and elevated cancer risk. - Additional repair pathways and specialized polymerases can participate when lesions persist, but the efficiency and accuracy of repair determine cellular outcomes after UV exposure.

Health implications and public health considerations - The accumulation of thymine dimers in skin cells is a key biochemical link between UV exposure and skin cancer risk, including Melanoma and other forms of Skin cancer. - Protective strategies that reduce UV-induced dimer formation—such as protective clothing, seeking shade, and the use of sunscreens—are standard public health recommendations. These measures lower the burden of CPDs and other UV-induced DNA lesions, contributing to lower long-term cancer risk. - Individual susceptibility varies with genetic factors that influence DNA repair capacity, pigmentation, and other aspects of the UV response. Understanding these factors helps explain differences in cancer risk among populations and individuals.

Occurrence across organisms - Thymine dimers and the corresponding repair responses are conserved across life, with bacterial and plant systems often relying on photoreactivation in addition to, or instead of, NER. In higher eukaryotes, including humans, NER is the primary defense, with photoreactivation playing a much smaller role. - The study of thymine dimers has illuminated fundamental principles of DNA repair, transcription-coupled repair, and the balance between genome stability and evolutionary adaptation in response to environmental UV stress.

See also - Ultraviolet radiation - DNA damage - Nucleotide excision repair - Photoreactivation - DNA replication - Mutation - Xeroderma pigmentosum - Cyclobutane pyrimidine dimer - 6-4 photoproduct - Skin cancer - Melanoma