User:BigPoppa1923/Pyrimidine dimer

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 * 1) Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions, commonly associated with direct DNA damage. 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. The photo-coupled dimers are fluorescent. 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. It causes sunburn and it triggers the production of melanin. Pyrimidine dimers are the primary cause of melanomas in humans.
 * 2) Pyrimidine dimers introduce local conformational changes in the DNA structure, which allow recognition of the lesion by repair enzymes. In most organisms (excluding placental mammals such as humans) they can be repaired by photoreactivation. 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.
 * 3) Nucleotide excision repair, sometimes termed "dark reactivation", 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. 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.
 * 4) Direct DNA damage is reduced by sunscreen. This prevents 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.

1. Pyrimidine dimers are molecular lesions formed  between  thymine or cytosine bases in DNA via photochemical reactions, and are commonly associated with direct DNA damage. 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. The photo-coupled dimers are fluorescent. 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. However, thymine dimers are much more common than cytosine dimers.

These premutagenic lesions can alter the structure '''of the DNA helix and cause non-canonical base pairing. Specifically, adjacent thymines of 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.'''  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. In humans, pyrimidine dimers are the primary cause of melanoma.'''

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.

2. Pyrimidine dimers introduce local conformational changes in the DNA structure, which allow recognition of the lesion by repair enzymes. In most organisms (excluding placental mammals such as humans) they can be repaired by photoreactivation. Photoreactivation is a repair process in which photolyase enzymes directly reverse CPDs via photochemical reactions. '''In addition, there are photolyases that 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. Bacteria and other prokaryotes utilize UV energy to directly excite this FAD molecule. The FAD molecule then gives an electron to the CPD, resulting in radical species of FAD and CPD. The CPD radical anion is then cleaved out and gives it's electron back to FAD, restoring FAD back to its original state.  In essence,  photolyases use energy from the sun to correct pyrimidine dimerization from UV light.'''

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. 3. Nucleotide excision repair (NER), sometimes termed "dark reactivation", is a more general mechanism of repair for 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. '''

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. ''' Some common features and symptoms of XP include skin discoloration, and the formation of multiple tumors proceeding UV exposure.

4. 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. '''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.'''

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''' Another type of repair mechanism that is conserved in humans and other non-mammals is translesion synthesis. Typically, the lesion associated with 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. '''