![DNA UV mutation](https://upload.wikimedia.org/wikipedia/commons/f/fd/DNA_UV_mutation.svg)
Pyrimidine dimers are
molecular lesion
A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in ...
s formed from
thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidi ...
or
cytosine
Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an ...
bases in
DNA via
photochemical reaction Organic photochemistry encompasses organic reactions that are induced by the action of light. The absorption of ultraviolet light by organic molecules often leads to reactions. In the earliest days, sunlight was employed, while in more modern times ...
s, commonly associated with direct DNA damage.
Ultraviolet light
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 Hertz, PHz) to 400 nm (750 Hertz, THz), shorter than that of visible light, but longer than ...
(UV; particularly
UVB
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
) induces the formation of
covalent
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
linkages between consecutive bases along the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
chain in the vicinity of their carbon–carbon double bonds. The
dimerization reaction can also occur among
pyrimidine bases in
dsRNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
(double-stranded RNA)—
uracil
Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
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
Photolyases () are DNA repair enzymes that repair damage caused by exposure to ultraviolet light. These enzymes require visible light (from the violet/blue end of the spectrum) both for their own activation and for the actual DNA repair. The DN ...
reactivation or
nucleotide excision repair. Uncorrected lesions can inhibit
polymerases, cause misreading during
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
or
replication, or lead to arrest of replication. It causes
sunburn
Sunburn is a form of radiation burn that affects living tissue, such as skin, that results from an overexposure to ultraviolet (UV) radiation, usually from the Sun. Common symptoms in humans and animals include: red or reddish skin that is ho ...
and it triggers the production of
melanin
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
.
Pyrimidine dimers are the primary cause of
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
s in humans.
Types of dimers
![Thymine photodimer](https://upload.wikimedia.org/wikipedia/commons/1/13/Thymine_photodimer.svg)
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. Such dimers interfere with base pairing during
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
, leading to mutations.
A 6–4 photoproduct (6–4 pyrimidine–
pyrimidone
Pyrimidone is the name given to either of two heterocyclic compounds with the formula C4H4N2O: 2-pyrimidone and 4-pyrimidone. The compounds can also be called ''2-hydroxypyrimidine'' or ''4-hydroxypyrimidine'' respectively, based on a substitute ...
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. This type of conversion occurs at one third the frequency of CPDs but is more mutagenic.
A third type of lesion is a
Dewar pyrimidinone, formed by a reversible
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
ization of the 6–4 photoproduct upon further exposure to light.
Skin light exposure
Due to the excellent photochemical properties of DNA, this nature-made molecule is damaged by only a tiny fraction of the absorbed photons. DNA transforms more than 99.9% of the photons into harmless heat
(but the damage from the remaining < 0.1% is still enough to cause sunburn).
The transformation of excitation energy into harmless heat occurs via a photochemical process called
internal conversion
Internal conversion is a non-radioactive, atomic decay process where an excited nucleus interacts electromagnetically with one of the orbital electrons of an atom. This causes the electron to be emitted (ejected) from the atom. Thus, in internal ...
. In DNA, this internal conversion is extremely fast, and therefore efficient. This ultrafast (subpicosecond) internal conversion is a powerful
photoprotection
Photoprotection is the biochemical process that helps organisms cope with molecular damage caused by sunlight. Plants and other oxygenic phototrophs have developed a suite of photoprotective mechanisms to prevent photoinhibition and oxidative st ...
provided by single nucleotides.
However, the Ground-State Recovery is much slower (picoseconds) in G·C−DNA duplexes and hairpins. It is presumed to be even slower for double-stranded DNA in conditions of the nucleus.
The absorption spectrum of DNA shows a strong absorption for UVB radiation and a much lower absorption for UVA radiation. Since the action spectrum of sunburn is indistinguishable from the absorption spectrum of DNA, it is generally accepted that the direct DNA damages are the cause of sunburn.
While the human body reacts to direct DNA damages with a painful warning signal,
no such warning signal is generated from
indirect DNA damage
Indirect, the opposite of direct, may refer to:
* Indirect approach, a battle strategy
* Indirect DNA damage, caused by UV-photons
*Indirect agonist or indirect-acting agonist, a substance that enhances the release or action of an endogenous neurot ...
.
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.
DNA repair
![melanoma](https://upload.wikimedia.org/wikipedia/commons/6/6c/Melanoma.jpg)
Pyrimidine dimers introduce local conformational changes in the
DNA structure
Nucleic acid structure refers to the structure of nucleic acids such as DNA and RNA. Chemically speaking, DNA and RNA are very similar. Nucleic acid structure is often divided into four different levels: primary, secondary, tertiary, and quat ...
, which allow recognition of the lesion by repair enzymes. In most organisms (excluding
placental mammals
Placental mammals (infraclass Placentalia ) are one of the three extant subdivisions of the class Mammalia, the other two being Monotremata and Marsupialia. Placentalia contains the vast majority of extant mammals, which are partly distinguishe ...
such as humans) they can be repaired by photoreactivation. Photoreactivation is a repair process in which
photolyase
Photolyases () are DNA repair enzymes that repair damage caused by exposure to ultraviolet light. These enzymes require visible light (from the violet/blue end of the spectrum) both for their own activation and for the actual DNA repair. The DN ...
enzymes directly reverse CPDs via
photochemical
Photochemistry is the branch of chemistry concerned with the chemical effects of light. Generally, this term is used to describe a chemical reaction caused by absorption of ultraviolet (wavelength from 100 to 400 nm), visible light (400–7 ...
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.
The UV dose that reduces a population of wild-type yeast cells to 37% survival is equivalent (assuming a
Poisson distribution
In probability theory and statistics, the Poisson distribution is a discrete probability distribution that expresses the probability of a given number of events occurring in a fixed interval of time or space if these events occur with a known co ...
of hits) to the UV dose that causes an average of one lethal hit to each of the cells of the population.
[Cox B, Game J. Repair systems in Saccharomyces. Mutat Res. 1974 Aug;26(4):257-64. doi: 10.1016/s0027-5107(74)80023-0. PMID: 4605044] The number of pyrimidine dimers induced per
haploid genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
at this dose was measured as 27,000.
[ 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.][ 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. This process excises the CPD and synthesizes new DNA to replace the surrounding region in the molecule.] Xeroderma pigmentosum
Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in su ...
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
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
. Unrepaired pyrimidine dimers in humans may lead to melanoma.
A few organisms have other ways to perform repairs:
* Spore photoproduct lyase
Spore photoproduct lyase (''SP lyase'', ''SPL'', ''SplB'', ''SplG'') is a radical SAM enzyme that repairs DNA cross linking of thymine bases caused by UV-radiation. There are several types of thymine cross linking, but SPL specifically targets 5 ...
is found in spore-forming bacteria. It returns thymine dimers to their original state.
* Deoxyribodipyrimidine endonucleosidase is found in bacteriophage T4
Escherichia virus T4 is a species of bacteriophages that infect ''Escherichia coli'' bacteria. It is a double-stranded DNA virus in the subfamily '' Tevenvirinae'' from the family Myoviridae. T4 is capable of undergoing only a lytic lifecycle ...
. It is a base excision repair
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
enzyme specific for pyrimidine dimers. It is then able to cut open the AP site
In biochemistry and molecular genetics, an AP site (apurinic/apyrimidinic site), also known as an abasic site, is a location in DNA (also in RNA but much less likely) that has neither a purine nor a pyrimidine base, either spontaneously or due ...
.
Sunscreen and melanoma
A study by Hanson suggests sunscreen that penetrates into the skin and thereby amplifies the amount of free radicals and oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
contributes to the formation of melanoma, but this idea has not been validated by other researchers.
Effect of topical sunscreen and effect of absorbed sunscreen
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.[{{cite journal , vauthors=Gulston M, Knowland J , date=July 1999 , title= 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 , journal=Mutat. Res. , volume= 444 , issue=1 , pages=49–60 , pmid=10477339 , doi=10.1016/s1383-5718(99)00091-1]
See also
*DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
References
DNA
Mutation
Dimers (chemistry)
DNA replication and repair-deficiency disorders
Senescence
Cyclobutanes