DNA Damage and Repair
Uploaded by
Biofilm NSTUDNA Damage and Repair
Uploaded by
Biofilm NSTUDNA Damage and Repair
Introduction to DNA Damage and Repair:
The maintenance of genome integrity and fidelity is essential for the proper function and survival
of all organisms. Though DNA is a highly stable and versatile molecule, sometimes damages
happened due to various reasons which lead to mutation. DNA may be modified in a variety of
ways, which can ultimately lead to mutations and genomic instability. This could result in the
development of a variety of cancers.
Causes of damage DNA:
1. Highly reactive oxygen radicals produced during normal cellular respiration (!) as well
as other biochemical pathways
a. Ionizing radiation: Gamma rays and X rays
b. UV radiation, especially by UV-C rays that are absorbed strongly by DNA cause strand
breaks. This involves a cut in one or both DNA strands.
[UV-induced damage can also result in the production of pyrimidine dimers, where covalent
cross-links occur in cytosine and thymine residues. Pyrimidine dimers can
disrupt polymerases and prevent proper replication of DNA]
2. Chemicals in the environment
a. Many hydrocarbons especially some found in smoke some plant and microbial products
such as Aflatoxin produced in moldy peanuts
b. Chemicals used in chemotherapy: DNA damage may also result from exposure
to polycyclic aromatic hydrocarbons (PAHs). PAHs are potent, ubiquitous atmospheric
pollutants commonly associated with oil, coal, cigarette smoke, and automobile exhaust
fumes.
[A common marker for DNA damage due to PAHs is Benzo pyrene diol epoxide (BPDE).
BPDE is found to be very reactive, and known to bind covalently to proteins, lipids, and guanine
residues of DNA to produce BPDE adducts. If left unrepaired, BPDE-DNA adducts may lead to
permanent mutations resulting in cell transformation and ultimately tumor development.]
3. Replication errors: Malfunction of the process of replication can lead to incorporation
of wrong bases, which are mismatched with the complementary strand.
4.
5.
The damage types of DNA are:
Damage to DNA includes any deviation from the usual double helix structure.
1. Simple Mutations
2. Deamination
3. Missing Bases
4. Chemical Modification of Bases
5. Formation of Pyrimidine Dimers (Thymine Dimers) and
6. Strand Breaks.
1. Simple Mutations:
Simplest mutations are switching of one base for another base. In transition one pyrimidine (C,T)
is substituted by another pyramidine and purine (A, G) with another purine. Trans-version
involves substitution of a pyramidine by a purine and purine by a pyrimidine such as T by G or
A and A by C or T.
Other simple mutations are detection, insertion of a single nucleotide or a small number of
nucleotides. Mutations which change a single nucleotide are called point mutations.
Figure: Point Mutation
2. Deamination:
Deamination occurs within the cell with the loss of amine groups from adenine, guanine , and
cytosine rings, resulting in hypoxanthine, xanthine, and uracil, respectively. DNA repair
enzymes are able to recognize and correct these unnatural bases.
The common alteration of form or damage includes deamination of cytosine (C) to form uracil
(U) which base pairs with adenine (A) in next replication instead of guanine (G) with which the
original cyto sine would have paired.
As uracil is not present in DNA, adenine base pairs with thymine (T). Therefore C-G pair is
replaced by T-A in next replication cycle. Similarly, hypoxanthine (purine) results from adenine
deamination
.
3. Missing Bases:
Cleavage of N-glycosidic bond between purine and sugar causes loss of purine base from DNA.
This is called depurination.
4. Chemical Modification of Bases:
Chemical modification of any of the four bases of DNA leads to modified bases. Methyl groups
are added to various bases. Guanine forms 7- methylguanine, 3-methylguanine. Adenine forms
3-methyladenine. Cytosine forms 5- Methylcytosine. Replacement of amino group by a keto
group converts 5-methylcytosine to thymine.
5. Formation of Pyrimidine Dimers (Thymine Dimers):
Formation of thymine dimers is very common in which a covalent bond (cyclobutyl ring) is
formed between adjacent thymine bases. This leads to loss of base pairing with opposite stand. A
bacterium may have thousands of dimers immediately after exposure to ultraviolet radiations.
6. Strand Breaks:
Sometimes phosphodiester bonds break in one strand of DNA helix. This is caused by various
chemicals like peroxides, radiations and by enzymes like DNases. This leads to breaks in DNA
backbone. Single strand breaks are more common than double strand breaks.
Sometimes X-rays, electronic beams and other radiations may cause phosphodiester bonds
breaks in both strands which may not be directly opposite to each other. This leads to double
strand breaks. Some sites on DNA are more susceptible to damage. These are called hot-stops.
