Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions.[1][2] Ultraviolet light induces the formation of covalent linkages by reactions localized on the C=C double bonds.[3] Two common UV products are cyclobutane pyrimidine dimers (CPDs, including thymine dimers) and 6,4 photoproducts. These premutagenic lesions alter the structure of DNA and consequently inhibit polymerases and arrest replication. Dimers may be repaired by photoreactivation or nucleotide excision repair, but unrepaired dimers are mutagenic. In humans they are the primary cause of melanomas.
Types of dimers edit
A cyclobutane pyrimidine dimer (CPD) contains a four membered ring arising from the coupling of the C=C double bonds of pyrimidines.[4][5][6] Such dimers interfere with base pairing during DNA replication, leading to mutations.
6,4-photoproducts, or 6,4 pyrimidine-pyrimidones, occur at one third the frequency of CPDs but are more mutagenic.[7] Spore photoproduct lyase provides another enzymatic pathway for repair of thymine photodimers.[8]
Cause of Dimerization-Solar Radiation edit
UV light is electromagnetic radiation with wavelengths shorter than 400 nm. The energy of a photon is directly related to and increases with frequency, so photons of UV light have more energy than those of visible or infrared light. High frequency UV light contains enough energy to cause mutation. The sun emits UV-A (400-315 nm), UV-B (315-280 nm) and UV-C (280-100 nm) radiation. The Earth's ozone layer, which is a low-density band of ozone (o3) in the stratosphere (10–50 km above the earth’s surface), acts as a filter to the UV-B and UV-C light, screening out all of the UV-C, and most of the UV-B. Therefore, 98.7% of the UV radiation that reaches the earth’s land and water surface is UV-A.
The depletion of the ozone layer allows a greater amount of the sun’s harmful ultra violet light to perforate our troposphere. In the 1980s, scientists warned that the ozone layer was being damaged by industrial chemicals, particularly a class of chemicals called chlorofluorocarbons (CFCs), used in factories and products such as aerosol cans and refrigeration equipment. Since then, the use of most of those chemicals has been phased out or restricted by law in the U.S. and many other countries.
Mutagenesis edit
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.[9]
DNA repair edit
Pyrimidine dimers introduce local conformational changes in the DNA structure, which allow recognition of the lesion by repair enzymes.[10] In most organisms (excluding placental mammals such as humans) they can be repaired by photoreactivation.[11]. Photoreactivation is a repair process in which photolyase enzymes directly reverse CPDs viaphotochemical 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.[12]
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. [13] 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, the most common human cancer[14]
References edit
- ^ 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.
- ^ E. C. Friedberg, G. C. Walker, W. Siede, R. D. Wood, R. A. Schultz and T. Ellenberger (2006). DNA repair and mutagenesis. Washington: ASM Press. p. 1118. ISBN 978-1555813192.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ 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:10.1034/j.1600-0781.2001.170502.x. PMID 11555330.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ R. B. Setlow (1966). "Cyclobutane-Type Pyrimidine Dimers in Polynucleotides". Science. 153 (3734): 379–386. doi:10.1126/science.153.3734.379.
- ^ Expert reviews in molecular medicine (2 December 2002). "Structure of the major UV-induced photoproducts in DNA" (PDF). Cambridge University Press.
- ^ Christopher Mathews and K.E. Van Holde (1990). Biochemistry (2nd ed.). Benjamin Cummings Publication. p. 1168. ISBN 978-0805350159.
- ^ Van Holde, K. E.; Mathews, Christopher K. (1990). Biochemistry. Menlo Park, Calif: Benjamin/Cummings Pub. Co. ISBN 0-8053-5015-2.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Jeffrey M. Buis, Jennifer Cheek, Efthalia Kalliri, and 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: 25994–26003. doi:10.1074/jbc.M603931200.
{{cite journal}}: Check|doi=value (help)CS1 maint: multiple names: authors list (link) - ^ J. H. Choi, A. Besaratinia ,D. H. Lee, C. S. Lee, G. P. Pfeifer (2006). "The role of DNA polymerase iota in UV mutational spectra". Mutat. Res. 599 (1–2): 58–65.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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 cis-syn thymine dimer”. European Journal of Biochemistry 162, 31-43
- ^ Essen LO, Klar T. (2006). Light-driven DNA repair by photolyases. Cell Mol Life Sci 63 (11), 1266-77.
- ^ Friedberg, Errol C. (23 January 2003) “DNA Damage and Repair”. Nature 421, 436-439. doi:10.1038/nature01408
- ^ Friedberg, Errol C. (23 January 2003) “DNA Damage and Repair”. Nature 421, 436-439. doi:10.1038/nature01408
- ^ Vink, Arie A.; Roza, Len (2001) “Biological consequences of cyclobutane pyrimidine dimers”. Journal of Photochemistry and Photobiology B: Biology 65, 101-104