Pyrimidine dimersrepresentmolecular lesionsoriginating fromthymineorcytosinebases withinDNA,resulting fromphotochemical reactions.[1][2]These lesions, commonly linked todirect DNA damage,[3]are induced byultraviolet light(UV), particularlyUVC,result in the formation ofcovalent bondsbetween adjacent nitrogenous bases along thenucleotidechain near their carbon–carbon double bonds,[4]the photo-coupled dimers arefluorescent.[5]Suchdimerization,which can also occur indouble-stranded RNA(dsRNA) involvinguracilorcytosine,leads to the creation ofcyclobutane pyrimidine dimers(CPDs) and6–4 photoproducts.These pre-mutageniclesions modify theDNA helixstructure, resulting in abnormal non-canonicalbase pairingand, consequently, adjacent thymines or cytosines in DNA will form acyclobutanering when joined together and cause a distortion in the DNA. This distortion preventsDNA replicationandtranscriptionmechanisms beyond the dimerization site.[6]
While up to 100 such reactions per second may transpire in askin cellexposed to sunlight resulting inDNA damage,they are typically rectified promptly throughDNA repair,such as throughphotolyasereactivation ornucleotide excision repair,with the latter being prevalent in humans. Conversely, certain bacteria utilize photolyase, powered by sunlight, to repair pyrimidine dimer-induced DNA damage. Unrepaired lesions may lead to erroneous nucleotide incorporation bypolymerasemachinery. Overwhelming DNA damage can precipitatemutationswithin an organism'sgenome,potentially culminating incancercell formation.[7]Unrectified lesions may also interfere with polymerase function, induce transcription orreplication errors,or halt replication. Notably, pyrimidine dimers contribute tosunburnandmelaninproduction, and are a primary factor inmelanomadevelopment in humans.
Types of pyrimidine dimers
editPyrimidine dimers encompass several types, each with distinct structures and implications for DNA integrity.[citation needed]
Cyclobutane pyrimidine dimer (CPD) is a dimer which features a four-membered ring formed by the fusion of two double-bonded carbons from adjacent pyrimidines. CPDs disrupt the formation of thebase pairduringDNA replication,potentially leading tomutations.[8][9][10]
The 6–4 photoproduct (6–4 pyrimidine–pyrimidone,or 6–4 pyrimidine–pyrimidinone) is an alternate dimer configuration consisting of a single covalent bond linking the carbon at the 6 (C6) position of one pyrimidine ring and carbon at the 4 (C4) position of the adjoining base's ring.[11]This type of conversion occurs at one third the frequency of CPDs and has a highermutagenicrisk.[12]
A third type of molecular lesion is aDewarpyrimidinone, resulting from the reversibleisomerizationof a 6–4 photoproduct under further light exposure.[13]
Mutagenesis
editMutagenesis, the process of mutation formation, is significantly influenced by translesionpolymeraseswhich often introduce mutations at sites of pyrimidine dimers. This occurrence is noted both inprokaryotes,through theSOS responseto mutagenesis, and ineukaryotes.Despite thymine-thymine CPDs being the most common lesions induced by UV, translesion polymerases show a tendency to incorporateadenines,resulting in the accurate replication of thymine dimers more often than not. Conversely, cytosines that are part of CPDs are susceptible todeamination,leading to a cytosine to thymine transition, thereby contributing to the mutation process.[14]
DNA repair
editPyrimidine dimers introduce local conformational changes in theDNA structure,which allow recognition of the lesion by repair enzymes.[15]In most organisms (excludingplacental mammalssuch as humans) they can be repaired by photoreactivation.[16]Photoreactivation is a repair process in whichphotolyaseenzymes reverse CPDs usingphotochemicalreactions. In addition, some photolyases can also repair 6-4 photoproducts of UV induced DNA damage. Photolyase enzymes utilizeflavin adenine dinucleotide (FAD)as a cofactor in the repair process.[17]
The UV dose that reduces a population of wild-type yeast cells to 37% survival is equivalent (assuming aPoisson distributionof hits) to the UV dose that causes an average of one lethal hit to each of the cells of the population.[18]The number of pyrimidine dimers induced perhaploidgenomeat this dose was measured as 27,000.[18]A mutant yeast strain defective in the three pathways by which pyrimidine dimers were known to berepairedin 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.[18]These findings thus indicate that the repair of thymine dimers in wild-type yeast is highly efficient.[citation needed]
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.[citation needed]
A few organisms have other ways to perform repairs:
- Spore photoproduct lyaseis found in spore-forming bacteria. It returns thymine dimers to their original state.[19]
- Deoxyribodipyrimidine endonucleosidaseis found inbacteriophage T4.It is abase excision repairenzyme specific for pyrimidine dimers. It is then able to cut open theAP site.
Another type of repair mechanism that is conserved in humans and other non-mammals istranslesion 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.[20]
Effect of topical sunscreen and effect of absorbed sunscreen
editDirect 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.[21]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.[22]
See also
editReferences
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- ^Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T, eds. (2006).DNA repair and mutagenesis.Washington: ASM Press. p. 1118.ISBN978-1-55581-319-2.
- ^Peak MJ, Peak JG (October 1991).Effects of Solar Ultraviolet Photons on Mammalian Cell DNA(PDF).Proceedings of the Symposium. Atlanta, Georgia, USA.
- ^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.PMID11555330.S2CID11529493.
- ^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.doi:10.1016/j.jphotochem.2022.114484.S2CID254622477.
- ^abCooper GM (2000)."DNA Repair".The Cell: A Molecular Approach(2nd ed.). Sinauer Associates.
- ^abKemp 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.PMC3442910.PMID22825251.
- ^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.PMID5328566.S2CID11210761.
- ^"Structure of the major UV-induced photoproducts in DNA"(PDF).Expert reviews in molecular medicine.Cambridge University Press. 2 December 2002. Archived fromthe original(PDF)on 21 March 2005.
- ^Mathews C, Van Holde KE (1990).Biochemistry(2nd ed.). Benjamin Cummings Publication. p.1168.ISBN978-0-8053-5015-9.
- ^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.PMC321925.PMID4034399.
- ^Van Holde KE, Mathews CK (1990).Biochemistry.Menlo Park, Calif: Benjamin/Cummings Pub. Co.ISBN978-0-8053-5015-9.[pages needed]
- ^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.
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