Pyrimidine dimer

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Main article: Pyrimidine

Formation of thymine dimer lesion in DNA. The photon causes two consecutive bases on one strand to bind together, destroying the normal base-pairing double-strand structure in that area. DNA UV mutation.svg
Formation of thymine dimer lesion in DNA. The photon causes two consecutive bases on one strand to bind together, destroying the normal base-pairing double-strand structure in that area.

A pyrimidine dimer is a type of molecular lesion that arises when adjacent thymine or cytosine bases are bonded together in an atypical way, often as a result of a photochemical reaction. [1] [2] Ultraviolet light (UV), [3] particularly UVC, often causes this direct DNA damage, causing the formation of covalent bonds near the nucleotides' carbon–carbon double bonds. [4] The resulting photo-coupled dimers are fluorescent, [5] and are commonly classified as cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts. These pre-mutagenic lesions modify the DNA helix structure by distorting it.

Contents

Up to 100 dimerization reactions per second can occur in a skin cell exposed to sunlight, [6] resulting in DNA damage. However, these lesions are typically rectified by DNA repair mechanisms before they can cause lasting damage. These mechanisms include photolyase reactivation and nucleotide excision repair, the latter of which is prevalent in humans. A failure to quickly repair these lesions may lead to erroneous (non-canonical) nucleotide incorporation by polymerase machinery. [7] Extreme DNA damage can precipitate mutations within an organism's genome, potentially culminating in cancer cell formation. [8] These lesions may also interfere with polymerase function, induce transcription or replication errors, or halt replication. [9]

Pyrimidine dimers contribute to sunburn and melanin production, and are a primary factor in melanoma development in humans. [10]

Types of pyrimidine dimers

Cyclobutane dimer (CPD) (left), 6,4-dimer (6-4PP) (right) CPD & 6-4PP thymidine photodimer.svg
Cyclobutane dimer (CPD) (left), 6,4-dimer (6-4PP) (right)

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. [11] [12] [13]

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. [14] This type of conversion occurs at one third of the frequency of CPDs but has a higher mutagenic risk. [15]

A Dewar pyrimidinone results from the reversible isomerization of a 6–4 photoproduct under further light exposure. [16]

Mutagenesis

Mutagenesis, the process of mutation formation, is significantly influenced by translesion polymerases which often introduce mutations at sites of pyrimidine dimers [17] . 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. [18]

DNA repair

Melanoma, a type of skin cancer Melanoma.jpg
Melanoma, a type of skin cancer

Pyrimidine dimers introduce local conformational changes in the DNA structure, which allows recognition of the lesion by repair enzymes. [19] In most organisms (excluding placental mammals such as humans) they can be repaired by photoreactivation. [20] 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. [21]

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. [22] The number of pyrimidine dimers induced per haploid genome at this dose was measured as 27,000. [22] 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. [22] These findings thus indicate that the repair of thymine dimers in wild-type yeast is highly efficient.[ citation needed ]

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. [9]

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. [8] Some common features and symptoms of XP include skin discoloration and the formation of multiple tumors proceeding UV exposure. [23]

A few organisms have other ways to perform repairs:

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. [25]

See also

References

  1. ↑ Goodsell DS (2001). "The molecular perspective: ultraviolet light and pyrimidine dimers". The Oncologist. 6 (3): 298–299. doi: 10.1634/theoncologist.6-3-298 . PMID   11423677. S2CID   36511461.
  2. ↑ Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T, eds. (2006). DNA repair and mutagenesis. Washington: ASM Press. p. 1118. ISBN   978-1-55581-319-2.
  3. ↑ Peak MJ, Peak JG (October 1991). Effects of Solar Ultraviolet Photons on Mammalian Cell DNA (PDF). Proceedings of the Symposium. Atlanta, Georgia, USA.
  4. ↑ Whitmore SE, Potten CS, Chadwick CA, Strickland PT, Morison WL (October 2001). "Effect of photoreactivating light on UV radiation-induced alterations in human skin". Photodermatology, Photoimmunology & Photomedicine. 17 (5): 213–217. doi:10.1111/j.1600-0781.2001.170502.x. PMID   11555330. S2CID   11529493.
  5. ↑ Carroll GT, Dowling RC, Kirschman DL, Masthay MB, Mammana A (2023). "Intrinsic fluorescence of UV-irradiated DNA". Journal of Photochemistry and Photobiology A. 437 114484. Bibcode:2023JPPA..43714484C. doi:10.1016/j.jphotochem.2022.114484. S2CID   254622477.
  6. ↑ Goodsell, David S. (2001-07-01). "The Molecular Perspective: Ultraviolet Light and Pyrimidine Dimers". STEM CELLS. 19 (4): 348–349. doi:10.1634/stemcells.19-4-348. ISSN   1066-5099.
  7. ↑ Laughery, Marian F.; Brown, Alexander J.; Bohm, Kaitlynne A.; Sivapragasam, Smitha; Morris, Haley S.; Tchmola, Mila; Washington, Angelica D.; Mitchell, Debra; Mather, Stephen; Malc, Ewa P.; Mieczkowski, Piotr A.; Roberts, Steven A.; Wyrick, John J. (2020-11-17). "Atypical UV Photoproducts Induce Non-canonical Mutation Classes Associated with Driver Mutations in Melanoma". Cell Reports. 33 (7). doi:10.1016/j.celrep.2020.108401. ISSN   2211-1247. PMC   7709870 . PMID   33207206.
  8. 1 2 Kemp MG, Sancar A (August 2012). "DNA excision repair: where do all the dimers go?". Cell Cycle. 11 (16): 2997–3002. doi:10.4161/cc.21126. PMC   3442910 . PMID   22825251.
  9. 1 2 Cooper GM (2000). "DNA Repair". The Cell: A Molecular Approach (2nd ed.). Sinauer Associates.
  10. ↑ Cleaver, James E.; Bootsma, D. (1975-12-01). "XERODERMA PIGMENTOSUM: BIOCHEMICAL AND GENETIC CHARACTERISTICS" . Annual Review of Genetics. 9 (9): 19–38. doi:10.1146/annurev.ge.09.120175.000315. ISSN   0066-4197.
  11. ↑ Setlow RB (July 1966). "Cyclobutane-type pyrimidine dimers in polynucleotides". Science. 153 (3734): 379–386. Bibcode:1966Sci...153..379S. doi:10.1126/science.153.3734.379. PMID   5328566. S2CID   11210761.
  12. ↑ "Structure of the major UV-induced photoproducts in DNA" (PDF). Expert reviews in molecular medicine. Cambridge University Press. 2 December 2002. Archived from the original (PDF) on 21 March 2005.
  13. ↑ Mathews C, Van Holde KE (1990). Biochemistry (2nd ed.). Benjamin Cummings Publication. p.  1168. ISBN   978-0-8053-5015-9.
  14. ↑ Rycyna RE, Alderfer JL (August 1985). "UV irradiation of nucleic acids: formation, purification and solution conformational analysis of the '6-4 lesion' of dTpdT". Nucleic Acids Research. 13 (16): 5949–5963. doi:10.1093/nar/13.16.5949. PMC   321925 . PMID   4034399.
  15. ↑ Van Holde KE, Mathews CK (1990). Biochemistry. Menlo Park, Calif: Benjamin/Cummings Pub. Co. pp. 868–870. ISBN   978-0-8053-5015-9.
  16. ↑ Taylor JS, Cohrs M (1987). "DNA, light and Dewar pyrimidinones: the structure and significance of TpT3". J. Am. Chem. Soc. 109 (9): 2834–2835. doi:10.1021/ja00243a052.
  17. ↑ 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/
  18. ↑ Choi JH, Besaratinia A, Lee DH, Lee CS, Pfeifer GP (July 2006). "The role of DNA polymerase iota in UV mutational spectra". Mutation Research. 599 (1–2): 58–65. Bibcode:2006MRFMM.599...58C. doi:10.1016/j.mrfmmm.2006.01.003. PMID   16472831.
  19. ↑ Kemmink J, Boelens R, Koning TM, Kaptein R, van der Marel GA, van Boom JH (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. 162 (1): 37–43. doi:10.1111/j.1432-1033.1987.tb10538.x. PMID   3028790.
  20. ↑ Essen LO, Klar T (June 2006). "Light-driven DNA repair by photolyases". Cellular and Molecular Life Sciences. 63 (11): 1266–1277. doi:10.1007/s00018-005-5447-y. PMC   11136382 . PMID   16699813. S2CID   5897571.
  21. ↑ Friedberg EC (January 2003). "DNA damage and repair". Nature. 421 (6921): 436–440. Bibcode:2003Natur.421..436F. doi: 10.1038/nature01408 . PMID   12540918.
  22. 1 2 3 Cox B, Game J (August 1974). "Repair systems in Saccharomyces". Mutation Research. 26 (4): 257–64. Bibcode:1974MRFMM..26..257C. doi:10.1016/s0027-5107(74)80023-0. PMID   4605044.
  23. ↑ Piccione, Monica; Belloni Fortina, Anna; Ferri, Giulia; Andolina, Gloria; Beretta, Lorenzo; Cividini, Andrea; De Marni, Emanuele; Caroppo, Francesca; Citernesi, Ugo; Di Liddo, Rosa (2021-11-04). "Xeroderma Pigmentosum: General Aspects and Management". Journal of Personalized Medicine. 11 (11): 1146. doi: 10.3390/jpm11111146 . ISSN   2075-4426. PMC   8624855 . PMID   34834498.
  24. ↑ Buis JM, Cheek J, Kalliri E, Broderick JB (September 2006). "Characterization of an active spore photoproduct lyase, a DNA repair enzyme in the radical S-adenosylmethionine superfamily". The Journal of Biological Chemistry. 281 (36): 25994–26003. doi: 10.1074/jbc.M603931200 . PMID   16829680.
  25. ↑ Takasawa K, Masutani C, Hanaoka F, Iwai S (2004-03-08). "Chemical synthesis and translesion replication of a cis–syn cyclobutane thymine–uracil dimer". Nucleic Acids Research. 32 (5): 1738–1745. doi:10.1093/nar/gkh342. PMC   390339 . PMID   15020710.
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