Biology:Pyrimidine dimer

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Short description: Type of damage to DNA
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] commonly associated with direct DNA damage.[3] Ultraviolet light (UV; particularly UVC) induces the formation of covalent linkages between consecutive bases along the nucleotide chain in the vicinity of their carbon–carbon double bonds.[4] The photo-coupled dimers are fluorescent.[5] 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 of the DNA helix and cause non-canonical base pairing. Specifically, adjacent thymines or cytosines in DNA will form a cyclobutane ring when joined together and cause a distortion in the DNA. This distortion prevents replication or transcription machinery beyond the site of the dimerization.[6] 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. In humans, the most common form of DNA repair is nucleotide excision repair (NER). In contrast, organisms such as bacteria can counterintuitively harvest energy from the sun to fix DNA damage from pyrimidine dimers via photolyase activity. If these lesions are not fixed, polymerase machinery may misread or add in the incorrect nucleotide to the strand. If the damage to the DNA is overwhelming, mutations can arise within the genome of an organism and may lead to the production of cancer cells.[7] Uncorrected lesions can inhibit polymerases, cause misreading during transcription or replication, or lead to arrest of replication. It causes sunburn and it triggers the production of melanin.[8] Pyrimidine dimers are the primary cause of melanomas in humans.

Types of dimers

Left: cyclobutane dimer (CPD). Right: 6,4-dimer (6-4PP)

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.[9][10][11] 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.[12] This type of conversion occurs at one third the frequency of CPDs but is more mutagenic.[13]

A third type of lesion is a Dewar pyrimidinone, formed by a reversible isomerization of the 6–4 photoproduct upon further exposure to light.[14]

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 cytosine involved in CPDs is prone to be deaminated, inducing a C to T transition.[15]

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.[16] In most organisms (excluding placental mammals such as humans) they can be repaired by photoreactivation.[17] 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.[18]

The UV dose that reduces a population of wild-type yeast cells to 37% survival is equivalent (assuming a Poisson distribution of hits) to the UV dose that causes an average of one lethal hit to each of the cells of the population.[19] The number of pyrimidine dimers induced per haploid genome at this dose was measured as 27,000.[19] A mutant yeast strain defective in the three pathways by which pyrimidine dimers were known to be repaired in yeast was also tested for UV sensitivity. It was found in this case that only one or, at most, two unrepaired pyrimidine dimers per haploid genome are lethal to the cell.[19] These findings thus indicate that the repair of thymine dimers in wild-type yeast is highly efficient.

Nucleotide excision repair, 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 strand to synthesize nucleotides off of and consequently fill in the gap on the previously damaged strand.[6]

Xeroderma pigmentosum (XP) is a rare genetic disease in humans in which genes that encode for NER proteins are mutated and result in decreased ability to combat pyrimidine dimers that form as a result of UV damage. Individuals with XP are also at a much higher risk of cancer than others, with a greater than 5,000 fold increased risk of developing skin cancers.[7] 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:

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, the CPD is bypassed by translesion polymerases, and replication and or transcription machinery can continue past the lesion. One specific translesion DNA polymerase, DNA polymerase η, is deficient in individuals with XPD.[21]

Effect of topical sunscreen and effect of absorbed sunscreen

Direct DNA damage is reduced by sunscreen, which also reduces the risk of developing a sunburn. When the sunscreen is at the surface of the skin, it filters the UV rays, which attenuates the intensity. Even when the sunscreen molecules have penetrated into the skin, they protect against direct DNA damage, because the UV light is absorbed by the sunscreen and not by the DNA.[22] Sunscreen primarily works by absorbing the UV light from the sun through the use of organic compounds, such as oxybenzone or avobenzone. These compounds are able to absorb UV energy from the sun and transition into higher-energy states. Eventually, these molecules return to lower energy states, and in doing so, the initial energy from the UV light can be transformed into heat. This process of absorption works to reduce the risk of DNA damage and the formation of pyrimidine dimers. UVA light makes up 95% of the UV light that reaches earth, whereas UVB light makes up only about 5%. UVB light is the form of UV light that is responsible for tanning and burning. Sunscreens work to protect from both UVA and UVB rays. Overall, sunburns exemplify DNA damage caused by UV rays, and this damage can come in the form of free radical species, as well as dimerization of adjacent nucleotides.[23]

See also

References

  1. ↑ "The molecular perspective: ultraviolet light and pyrimidine dimers". The Oncologist 6 (3): 298–299. 2001. doi:10.1634/theoncologist.6-3-298. PMID 11423677. 
  2. ↑ DNA repair and mutagenesis. Washington: ASM Press. 2006. p. 1118. ISBN 978-1-55581-319-2. 
  3. ↑ "Effects of Solar Ultraviolet Photons on Mammalian Cell DNA.". Proceedings of the Symposium. Atlanta, Georgia, USA. October 1991. http://www.osti.gov/bridge/servlets/purl/6106470-Syh9i7/6106470.PDF. 
  4. ↑ "Effect of photoreactivating light on UV radiation-induced alterations in human skin". Photodermatology, Photoimmunology & Photomedicine 17 (5): 213–217. October 2001. doi:10.1111/j.1600-0781.2001.170502.x. PMID 11555330. 
  5. ↑ "Intrinsic fluorescence of UV-irradiated DNA". Journal of Photochemistry and Photobiology A 437: 114484. 2023. doi:10.1016/j.jphotochem.2022.114484. 
  6. ↑ 6.0 6.1 "DNA Repair" (in en). The Cell: A Molecular Approach (2nd ed.). Sinauer Associates. 2000. https://www.ncbi.nlm.nih.gov/books/NBK9900/. 
  7. ↑ 7.0 7.1 "DNA excision repair: where do all the dimers go?". Cell Cycle 11 (16): 2997–3002. August 2012. doi:10.4161/cc.21126. PMID 22825251. 
  8. ↑ "Erythema and melanogenesis action spectra of normal human skin". Photochemistry and Photobiology 36 (2): 187–191. August 1982. doi:10.1111/j.1751-1097.1982.tb04362.x. PMID 7122713. 
  9. ↑ "Cyclobutane-type pyrimidine dimers in polynucleotides". Science 153 (3734): 379–386. July 1966. doi:10.1126/science.153.3734.379. PMID 5328566. Bibcode: 1966Sci...153..379S. 
  10. ↑ "Structure of the major UV-induced photoproducts in DNA.". Expert reviews in molecular medicine. Cambridge University Press. 2 December 2002. http://www-ermm.cbcu.cam.ac.uk/02005331a.pdf. 
  11. ↑ Biochemistry (2nd ed.). Benjamin Cummings Publication. 1990. p. 1168. ISBN 978-0-8053-5015-9. https://archive.org/details/biochemistry00math_0/page/1168. 
  12. ↑ "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. August 1985. doi:10.1093/nar/13.16.5949. PMID 4034399. 
  13. ↑ Biochemistry. Menlo Park, Calif: Benjamin/Cummings Pub. Co.. 1990. ISBN 978-0-8053-5015-9. https://archive.org/details/biochemistry00math_0. [pages needed]
  14. ↑ "DNA, light and Dewar pyrimidinones: the structure and significance of TpT3". J. Am. Chem. Soc. 109 (9): 2834–2835. 1987. doi:10.1021/ja00243a052. 
  15. ↑ "The role of DNA polymerase iota in UV mutational spectra". Mutation Research 599 (1–2): 58–65. July 2006. doi:10.1016/j.mrfmmm.2006.01.003. PMID 16472831. 
  16. ↑ "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. January 1987. doi:10.1111/j.1432-1033.1987.tb10538.x. PMID 3028790. 
  17. ↑ "Light-driven DNA repair by photolyases". Cellular and Molecular Life Sciences 63 (11): 1266–1277. June 2006. doi:10.1007/s00018-005-5447-y. PMID 16699813. 
  18. ↑ "DNA damage and repair". Nature 421 (6921): 436–440. January 2003. doi:10.1038/nature01408. PMID 12540918. Bibcode: 2003Natur.421..436F. 
  19. ↑ 19.0 19.1 19.2 "Repair systems in Saccharomyces". Mutation Research 26 (4): 257–64. August 1974. doi:10.1016/s0027-5107(74)80023-0. PMID 4605044. 
  20. ↑ "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. September 2006. doi:10.1074/jbc.M603931200. PMID 16829680. 
  21. ↑ "Chemical synthesis and translesion replication of a cis-syn cyclobutane thymine-uracil dimer". Nucleic Acids Research 32 (5): 1738–1745. 2004-03-08. doi:10.1093/nar/gkh342. PMID 15020710. 
  22. ↑ "Illumination of human keratinocytes in the presence of the sunscreen ingredient Padimate-O and through an SPF-15 sunscreen reduces direct photodamage to DNA but increases strand breaks". Mutation Research 444 (1): 49–60. July 1999. doi:10.1016/s1383-5718(99)00091-1. PMID 10477339. 
  23. ↑ "The efficacy and safety of sunscreen use for the prevention of skin cancer". CMAJ 192 (50): E1802–E1808. December 2020. doi:10.1503/cmaj.201085. PMID 33318091. 



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