DNA damage can occur endogenously through normal cellular processes like respiration or replication errors, or exogenously through environmental factors like radiation, chemicals, and alkylating agents used in chemotherapy. Common types of DNA damage include depurination, deamination of cytosine and adenine, alkylation of bases, insertion/deletions of nucleotides, base analog incorporation, cross-linkages induced by bifunctional alkylating agents and UV light, and oxidative free radical formation. This damage can lead to mutations in the DNA sequence, including point mutations like missense, nonsense, and silent mutations, or frameshift mutations involving insertions, deletions, or inversions.

1. DNA DAMAGE AND MUTATION

2. SOURCE OF DNA DAMAGE-
ENDOGENOUS DAMAGES –
● It includes damage from with in the cell.
● It also includes replication errors.
EXOGENOUS DAMAGES -
● Radiations
▪ Highly reactive oxygen radicals produced during normal cellular respiration as well as by other
biochemical pathways.
▪ Ionizing radiation.
▪ Ultraviolet rays.
● Chemical in the enviroment
▪ Aromatic hydrocarbons, including some found in the cigarette smoke.
▪ Plant and microbial products, e.g. the Aflatoxin produced in moldy peanuts.
▪ Chemical used in chemotherapy, especially chemotherapy of cancers.

3. DEPURINATION - DNA undergoes major changes
as a result of thermal fluctuations: for example,
about 5000 purine bases (adenine and guanine)
are lost every day from the DNA of each human
cell because their N-glycosyl linkages to
deoxyribose hydrolyze spontaneously.
Deamination of cytosine to uracil -
Spontaneous deamination is the hydrolysis
reaction of cytosine into uracil, releasing
ammonia in the process. In DNA, this
spontaneous deamination is corrected for by the
removal of uracil (product of cytosine
deamination and not part of DNA) by uracil-
DNA glycosylase, generating an a basic (AP) site .

4. DEAMINATION OF ADENINE TO HYPOXANTHINE –
Hypoxanthine is also a spontaneous deamination product
of adenine. Because of its resemblance to guanine, the
spontaneous deamination of adenine can lead to an error
in DNA transcription/replication, as it base pairs with cytosine.
ALKYLATION OF BASE - Alkylation lesions in DNA and RNA
result from endogenous compounds, environmental agents
and alkylating drugs. Bifunctional alkylating agents are
commonly used anti-cancer drugs. DNA lesions caused by
these agents are complex and require
complex repair mechanisms.
INSERTION OR DELETION OF NEUCLEOTIDE - When strand
slippage occurs during DNA replication, a DNA strand may loop
out, resulting in the addition or deletion of a nucleotide on the
newly-synthesized strand. But if this does not occur,
a nucleotide that is added to the newly synthesized strand can
become a permanent mutation.

5. BASE- ANALOG INCORPORATION – Environmental and intrinsic
mutagens can damage DNA directly or can damage DNA precursor
pools. When cleansing is inefficient, base-
analogs are incorporated into DNA. Damaged bases lead to mutations
in replication cycles or can be correctly repaired
by base excision repair.
BIFUNCTIONAL ALKYLATING AGENT CROSS-LINKAGE - For
this reason, DNA has become a critical target in cancer
chemotherapy. Bifunctional alkylating agents form covalent
bonds at two nucleophilic sites on different DNA bases to
induce interstrand (between two opposite strands) and/or
intrastrand (on same strand) cross-links .
UV LIGHT- INDUCED THYMINE-THYMINE (PYRIMIDINE) DIMER-
Thymine dimer is a photolesion produced by UV
radiation in sunlight and is considered as a potential
factor causing skin cancer. It is formed as a covalently bonded
complex of two adjacent thymines on a single strand of DNA.

6. IONIZING RADIATION –
onizing radiation is a type of high-energy radiation that is
able to release electrons from atoms and molecules
generating ions which can break covalent bonds. Ionizing
radiation directly affects DNA structure by
inducing DNA breaks.
OXIDATIVE FREE RADICAL FORMATION - Free radicals are
produced in cells by cellular metabolism and by exogenous
agents. These species react with biomolecules in cells,
including DNA. The resulting damage to DNA, which is also
called oxidative damage to DNA, is implicated in
mutagenesis, carcinogenesis.

7. DNA MUTATION - A mutation is a change in a DNA sequence. Mutations can result from DNA copying mistakes
made during cell division, exposure to ionizing radiation, exposure to chemicals called mutagens, or infection by
viruses .
POINT MUTATION - ● MISENSE MUTATION
●SILENT MUTATION
● NON- SENSE MUTATION
FRAME- SHIFT MUTATION - ● INSERTION
● DELETION
● INVERSION
POINT MUTATION – Point mutations are the single
– based mutations. ( a change in one neucleotide
of the sequence ).
MISENSE MUTATION – 1) The new codon causes an
incorrect amino acid to be inserted into the
protein.
2) This effect on the function of the protein depend
on what in place of normal amino acid.
DNA MUTATION

8. NON- SENSE MUTATION – The new codon causes the protein to permaturely
TERMINATE, producing a product that is shortened and often does not function.
SILENT MUTATION – Silent mutation does not causes any change in amino acid.
( silent mutation codes for same amino acid).
FRAME-SHIFT MUTATION – A frameshift mutation is a type of mutation
involving the insertion or deletion of a nucleotide in which the number of
deleted base pairs is not divisible by three .
INSERTIONS – Insertion is the addition of one or more bases to a
neucleitide sequence .
This mutation will alter the rest of the neucleotide
sequence and change arrangement of codons .
Deletion – Loss of part of chromosome .
INVERSION – Reverses direction of part of
chromosome .