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.
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