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Pyrimidine dimer

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.

Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions.[1][2] Ultraviolet light (UV) induces the formation of covalent linkages between consecutive bases along the nucleotide chain in the vicinity of their carbon–carbon double bonds.[3] The dimerization reaction can also occur among pyrimidine bases in dsRNA (double-stranded RNA)—uracil or cytosine. Two common UV products are cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts. These premutagenic lesions alter the structure and possibly the base-pairing. Up to 50–100 such reactions per second might occur in a skin cell during exposure to sunlight, but are usually corrected within seconds by photolyase reactivation or nucleotide excision repair. Uncorrected lesions can inhibit polymerases, cause misreading during transcription or replication, or lead to arrest of replication. Pyrimidine dimers are the primary cause[not verified in body] of melanomas in humans.

Types of dimers

A cyclobutane pyrimidine dimer (CPD) contains a four membered ring arising from the coupling of the two double-bonded carbons of each of the pyrimidines.[4][5][6] Such dimers interfere with base pairing during DNA replication, leading to mutations.

A 6–4 photoproduct (6–4 pyrimidine–pyrimidone or 6–4 pyrimidine–pyrimidinone) is an alternate dimer consisting of a single covalent bond between the carbon at the 6 position of one ring and carbon at the 4 position of the ring on the next base.[7] This type of conversion occurs at one third the frequency of CPDs but is more mutagenic.[8] Spore photoproduct lyase provides another enzymatic pathway for repair of thymine photodimers.[9]

A third type of lesion is a Dewar pyrimidinone, formed by a reversible isomerization of the 6–4 photoproduct upon further exposure to light.[10]

Mutagenesis

Translesion polymerases frequently introduce mutations at pyrimidine dimers, both in prokaryotes (SOS mutagenesis) and in eukaryotes. Although the thymine-thymine CPDs (thymine dimers) are the most frequent lesions caused by UV light, translesion polymerases are biased toward introduction of As, so that TT dimers are often replicated correctly. On the other hand, any C involved in CPDs is prone to be deaminated, inducing a C to T transition.[11]

DNA repair

Melanoma, a type of skin cancer

Pyrimidine dimers introduce local conformational changes in the DNA structure, which allow recognition of the lesion by repair enzymes.[12] In most organisms (excluding placental mammals such as humans) they can be repaired by photoreactivation.[13] Photoreactivation is a repair process in which photolyase enzymes directly reverse CPDs via photochemical reactions. Lesions on the DNA strand are recognized by these enzymes, followed by the absorption of light wavelengths >300 nm (i.e. fluorescent and sunlight). This absorption enables the photochemical reactions to occur, which results in the elimination of the pyrimidine dimer, returning it to its original state.[14]

Nucleotide excision repair is a more general mechanism for repair of lesions. This process excises the CPD and synthesizes new DNA to replace the surrounding region in the molecule.[14] Xeroderma pigmentosum is a genetic disease in humans in which the nucleotide excision repair process is lacking, resulting in skin discolouration and multiple tumours on exposure to UV light. Unrepaired pyrimidine dimers in humans may lead to melanoma.[15]

References

  1. ^ David S. Goodsell (2001). "The Molecular Perspective: Ultraviolet Light and Pyrimidine Dimers". The Oncologist. 6 (3): 298–299. doi:10.1634/theoncologist.6-3-298. PMID 11423677.
  2. ^ E. C. Friedberg; G. C. Walker; W. Siede; R. D. Wood; R. A. Schultz & T. Ellenberger (2006). DNA repair and mutagenesis. Washington: ASM Press. p. 1118. ISBN 978-1-55581-319-2.
  3. ^ S. E. Whitmore; C. S. Potten; C. A. Chadwick; P. T. Strickland; W. L. Morison (2001). "Effect of photoreactivating light on UV radiation-induced alterations in human skin". Photodermatol. Photoimmunol. Photomed. 17 (5): 213–217. doi:10.1111/j.1600-0781.2001.170502.x. PMID 11555330.
  4. ^ R. B. Setlow (1966). "Cyclobutane-Type Pyrimidine Dimers in Polynucleotides". Science. 153 (3734): 379–386. doi:10.1126/science.153.3734.379. PMID 5328566.
  5. ^ Expert reviews in molecular medicine (2 December 2002). "Structure of the major UV-induced photoproducts in DNA" (PDF). Cambridge University Press. Archived from the original (PDF) on 21 March 2005.
  6. ^ Christopher Mathews & K.E. Van Holde (1990). Biochemistry (2nd ed.). Benjamin Cummings Publication. p. 1168. ISBN 978-0-8053-5015-9.
  7. ^ R. E. Rycyna; J. L. Alderfer (1985). "UV irradiation of nucleic acids: formation, purification and solution conformational analysis of the '6–4 lesion' of dTpdT". Nucl. Acids. Res. 13: 5949–5963. PMID 4034399.
  8. ^ Van Holde, K. E.; Mathews, Christopher K. (1990). Biochemistry. Menlo Park, Calif: Benjamin/Cummings Pub. Co. ISBN 0-8053-5015-2.[pages needed]
  9. ^ Jeffrey M. Buis; Jennifer Cheek; Efthalia Kalliri & Joan B. Broderick (2006). "Characterization of an Active Spore Photoproduct Lyase, a DNA Repair Enzyme in the Radical S-Adenosylmethionine Superfamily". Journal of Biological Chemistry. 281 (36): 25994–26003. doi:10.1074/jbc.M603931200. PMID 16829680.
  10. ^ J.-S. Taylor; M. Cohrs (1987). "DNA, light and Dewar pyrimidinones: the structure and significance of TpT3". J. Am. Chem. Soc. 109 (9): 2834–2835. doi:10.1021/ja00243a052.
  11. ^ J. H. Choi; A. Besaratinia; D. H. Lee; C. S. Lee; G. P. Pfeifer (2006). "The role of DNA polymerase ι in UV mutational spectra". Mutat. Res. 599 (1–2): 58–65. doi:10.1016/j.mrfmmm.2006.01.003. PMID 16472831.
  12. ^ Kemmink Johan; Boelens Rolf; Koning Thea M.G.; Kaptein Robert; Van, der Morel Gijs A.; Van Boom Jacques H. (1987). "Conformational Changes in the oligonucleotide duplex d(GCGTTGCG)•d(GCGAAGCG) induced by formation of a cissyn thymine dimer". European Journal of Biochemistry. 162: 31–43. doi:10.1111/j.1432-1033.1987.tb10538.x. PMID 3028790.
  13. ^ Essen LO, Klar T (2006). "Light-driven DNA repair by photolyases". Cell Mol Life Sci. 63 (11): 1266–77. doi:10.1007/s00018-005-5447-y. PMID 16699813.
  14. ^ a b Errol C. Friedberg (23 January 2003). "DNA Damage and Repair". Nature. 421: 436–439. doi:10.1038/nature01408.
  15. ^ Vink Arie A.; Roza Len (2001). "Biological consequences of cyclobutane pyrimidine dimers". Journal of Photochemistry and Photobiology B: Biology. 65 (2–3): 101–104. doi:10.1016/S1011-1344(01)00245-7.