Pyrimidine dimer

Types of pyrimidine dimers

The different types of pyrimidine dimers each have distinct structures and implications for DNA integrity.

A cyclobutane dimer (CPD) features a four-membered ring formed by the fusion of two double-bonded carbons from adjacent pyrimidines. CPDs disrupt the formation of the base pair during DNA replication, which can potentially lead to mutations.

The 6–4 photoproduct (6–4 pyrimidine–pyrimidone, or 6–4 pyrimidine–pyrimidinone) is an alternate dimer configuration which covalently links the carbon at the 6 (C6) position of one pyrimidine ring and the carbon at the 4 (C4) position of the adjoining base's ring. This type of conversion occurs at one third of the frequency of CPDs but has a higher mutagenic risk.

A Dewar pyrimidinone results from the reversible isomerization of a 6–4 photoproduct under further light exposure.

Mutagenesis

Main article: Mutagenesis

Mutagenesis, the process of mutation formation, is significantly influenced by translesion polymerases which often introduce mutations at sites of pyrimidine dimers.Durland J, Ahmadian-Moghadam H. Genetics, Mutagenesis. [Updated 2022 Sep 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560519/ This occurs in prokaryotes through the SOS response to mutagenesis and in eukaryotes through other methods. As thymine–thymine CPDs are the most common lesions induced by UV, translesion polymerases show a tendency to incorporate adenines opposite these dimers, resulting in accurate replication. Cytosines that are part of CPDs, however, are susceptible to deamination, leading to cytosine to thymine transitions and contributing to the mutation process.

DNA repair

Pyrimidine dimers introduce local conformational changes in the DNA structure, which allows recognition of the lesion by repair enzymes. In most organisms (excluding placental mammals such as humans) they can be repaired by photoreactivation. Photoreactivation is a repair process in which photolyase enzymes reverse CPDs using photochemical reactions. In addition, some photolyases can also repair 6-4 photoproducts of UV induced DNA damage. Photolyase enzymes utilize flavin adenine dinucleotide (FAD) as a cofactor in the repair process.

The UV dose that reduces a population of wild-type yeast cells to 37% (assuming a Poisson distribution of hits) is the same as the UV dose that causes an average of one lethal hit to each of the cells of the population. The number of pyrimidine dimers induced per haploid genome at this dose was measured as 27,000. A mutant yeast strain defective in the three known pyrimidine dimer repair pathways was also tested for UV sensitivity. In this case, only one to two unrepaired pyrimidine dimers per haploid genome are lethal to the cell. These findings thus indicate that the repair of thymine dimers in wild-type yeast is highly efficient.

Nucleotide excision repair (NER), sometimes termed "dark reactivation", is a more general mechanism for repair of lesions and is the most common form of DNA repair for pyrimidine dimers in humans. This process works by using cellular machinery to locate the dimerized nucleotides and excise the lesion. Once the CPD is removed, there is a gap in the DNA strand that must be filled. DNA machinery uses the undamaged complementary DNA strand as a template to synthesize the matching nucleotides and consequently fill in the gap on the damaged strand.

Xeroderma pigmentosum (XP) is a rare genetic disease in humans that is caused by UV damage to genes that code for NER proteins, resulting in the inability for the cell to combat pyrimidine dimers that form. Individuals with XP are also at a much higher risk of cancer, with a 5,000-fold increased risk of developing skin cancers compared to the general population. Some common features and symptoms of XP include skin discoloration and the formation of multiple tumors proceeding UV exposure.

A few organisms have other ways to perform repairs:

• Spore photoproduct lyase is found in spore-forming bacteria. It reverts thymine dimers to their original state.
• Deoxyribodipyrimidine endonucleosidase is found in bacteriophage T4. It is a base excision repair enzyme specific for pyrimidine dimers, and is able to cut open the AP site. Another type of repair mechanism that is conserved in humans and other non-mammals is translesion synthesis. Typically, the lesion associated with the pyrimidine dimer blocks cellular machinery from synthesizing past the damaged site. However, in translesion synthesis, translesion polymerases can replicate past the CPD, allowing both replication and transcription machinery to continue past the lesion. One specific translesion DNA polymerase, DNA polymerase η, is deficient in individuals with Xeroderma pigmentosum.

References

References

1. (2006). "DNA repair and mutagenesis". ASM Press.
2. (October 1991). "Effects of Solar Ultraviolet Photons on Mammalian Cell DNA.".
3. (2023). "Intrinsic fluorescence of UV-irradiated DNA". Journal of Photochemistry and Photobiology A.
4. Goodsell, David S.. (2001-07-01). "The Molecular Perspective: Ultraviolet Light and Pyrimidine Dimers". Stem Cells.
5. (2020-11-17). "Atypical UV Photoproducts Induce Non-canonical Mutation Classes Associated with Driver Mutations in Melanoma". Cell Reports.
6. (August 2012). "DNA excision repair: where do all the dimers go?". Cell Cycle.
7. (2000). "The Cell: A Molecular Approach". Sinauer Associates.
8. (1975-12-01). "Xeroderma Pigmentosum: Biochemical and Genetic Characteristics". Annual Review of Genetics.
9. (July 1966). "Cyclobutane-type pyrimidine dimers in polynucleotides". Science.
10. (2 December 2002). "Structure of the major UV-induced photoproducts in DNA.". Expert reviews in molecular medicine.
11. (1990). "Biochemistry". Benjamin Cummings Publication.
12. (1990). "Biochemistry". Benjamin/Cummings Pub. Co..
13. (1987). "DNA, light and Dewar pyrimidinones: the structure and significance of TpT3". J. Am. Chem. Soc..
14. (July 2006). "The role of DNA polymerase iota in UV mutational spectra". Mutation Research.
15. (January 1987). "Conformational changes in the oligonucleotide duplex d(GCGTTGCG) x d(CGCAACGC) induced by formation of a ''cis''–''syn'' thymine dimer. A two-dimensional NMR study". European Journal of Biochemistry.
16. (June 2006). "Light-driven DNA repair by photolyases". Cellular and Molecular Life Sciences.
17. (January 2003). "DNA damage and repair". Nature.
18. (August 1974). "Repair systems in ''Saccharomyces''". Mutation Research.
19. (2021-11-04). "Xeroderma Pigmentosum: General Aspects and Management". Journal of Personalized Medicine.
20. (September 2006). "Characterization of an active spore photoproduct lyase, a DNA repair enzyme in the radical ''S''-adenosylmethionine superfamily". The Journal of Biological Chemistry.
21. (2004-03-08). "Chemical synthesis and translesion replication of a ''cis''–''syn'' cyclobutane thymine–uracil dimer". Nucleic Acids Research.