Ultraviolet Mutagenesis

Ultraviolet light (UV)

UV light, an electromagnetic radiation with a wavelength range between 400 nm to 10 nm, i.e. shorter and longer than visible light and X-ray.

Natural source of UV light is sun and its artificial emitted by electric arcs or by mercury lamps.

It has a strong genotoxic effects to produce DNA damage, induce mutations and causes tumor development. It also said to be the main cause of skin cancer.

Purines and pyrimidine absorbs UV at 260 nm wavelength, which makes a perfect source for identifying nucleic acids in Electrophoresis. 

There three bands of UV classified based on their wavelength: UVA àUVA1 (340-400 nm); UVA2 (320-340 nm), UVB à (290-400nm).  UVB is has the strong carcinogenic effect on skin. And UVA has some role in skin carcinogenesis.

UV Induced DNA lesions

A lesion in the DNA means the weak hydrogen bonds in the base pair denatures, which leads to instability in the DNA structure. It can be an abnormal base in the DNA or damage to the sugar-phosphate backbone.

UV induces DNA lesions by the two ways:

By producing photoproducts

UV photons are easily absorbed by the DNA molecules and an excited state is produced which allows rearrangement of electrons resulting in the formation of photoproducts. cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6-4)pyrimidone (64PPs) are the photoproducts formed by the UVB radiation. These photoproducts are found to be the cause of UV-specific mutations.

By producing ROS

And UV can also induce oxidative stress in the irradiated cells through the production of reactive oxygen species (ROS) by activating small molecules such as riboflavin, tryptophan and porphyrin. This will further activate the cellular oxygen.

DNA exposed to these ROS will produce oxidative base damage such as 8-hydroxyguanine (8OH-G) and thym­ine glycol in DNA or can make strand breaks.  ROS also attack cellular nucleotide pools, producing oxidized nucle­otides such as 8-hydroxydeoxygunanosine-triphosphate (8OH-dGTP), which can still be used as nucleotide precursors for DNA synthesis.

UV induced mutation

UV photons are absorbed by the DNA molecular and therefore pyrimidine dimers (Thymine-thymine dimers) are formed. During this moment, the DNA repair mechanism works and correct the dimer units. But in some cases mutation occurs, which is basically meant as DNA repair error.

Two types of mutations are induced by UV:

1) Base substitution of Cytosine à Thymine at dipyrimidine site.

2) Tandem base substitution of cytosine-cytosine à thymine-thymine.

These two types of mutations are best known to be UV signatures, because detection of these mutations suggests the past exposure to UV.

UV mutation by Deamination

Cytosine containing CPDs are quite unstable and they are easily deaminated to uracil. So, the uracil containing CPD are the causative agent for DNA damage.

In Deamination process, an amino group is converted to a keto group in cytosine and adenine. In that case, cytosine is converted to uracil and adenine is converted to hypoxanthine. So this will alter the base-pairing specificities of these two bases during replication. i.e Normally Cytosine pairing with thymine, but after deaminated to uracil, it will now pair with adenine. Then further replication process will replace the uracil to thymine. The same case goes for adenine which gets converted to hypoxanthine, which has affinity for cytosine.

Translesion DNA synthesis (TLS)

Actually, these photoproducts such as CPDs, 64PPs and dewar isomer block the DNA synthesis by preventing the replicative DNA polymerase from passing them when they reside on a template strand during DNA replication. Nucleotide excision repair which is a DNA repair mechanism tries to excise these photolesions, but sometimes failure in the repair before replication fork passing would lead to stall and collapse of the fork at the damaged site. Thus it leads to DNA double strand break and cell death eventually.

Inorder to overcome these conditions, Translesion DNA synthesis process will overcome this replication blocks and save the cell from death. In this process, TLS polymerase enzyme restarts the DNA syn­thesis been stalled at obstructive, damaged bases on a template strand. It is meant to be error prone and it introduces mutation in the genome at high frequency.

But somehow DNA polymerase (pol) η suppresses efficiently the induction of mutations after UV irradiation by performing an error-free TLS opposite CPDs using the base-pairing ability still remaining for CPDs.

Patient with pol η are prone to this UV radiation and they show high photocarcinogenic sensitivity in skin regions exposed to sunlight. Therefore pol η is consider as a suppressor for CPD mediated mutation. But unintentionally, it will produce the UV signature mutation produced by the deamination process.