DNA MUTATION AND DNA REPAIR

Mutation is the alteration in gene sequence.

1Hereditary (mutation on the germline)
2Change in structure of nucleotide sequence of the DNA

a. Mutation can be spontaneous or induced.

b. Mutation according to size:

Point mutation
Gross Chromosomal mutation

Effects:
1Lethal
2Branching in the evolutionary tree or specie diversity

Point Mutation
A.Substitution mutation
- single-base mutations, substitution of one or more nucleotides by the same number of different
nucleotides.
Types: Transition and Transversion
Transition
purine to purine
A → G

pyrimidine to pyrimidine
C → T

Transversion
purine to pyrimidine (vice-versa)
A → C G → C
A → T G → T

Consequences:
1.SILENT MUTATION – no effect on the amino acid sequence of the protein.
Ex: CAG → CAA
Gln → Gln

2.MISSENSE MUTATION – results in the incorporation of a different amino acid in the protein. The
protein may be functional, partially functional or non-functional.
CAG → CAC
Gln → His

3.NONSENSE MUTATION – results in the premature appearance of the stop codon resulting to a
shortened protein that is likely to be non-functional.
CAG → TAG
Gln → Stop

B.Deletion Mutation – removal of one or more nucleotides in the DNA.

Consequence of Deletion:
FRAMESHIFT MUTATION – a shift in the reading frame, which produces a non-functional protein
 ATT GGC AAA GCA TCA AAC TTA GGG CCC

deletion of G at
codon 4

ATT GGC AAA CAT CAA ACT TAG GGC CC…

--- reading frame was changed

C.Insertion Mutation – addition of one or more nucleotides in the DNA

Consequence of Deletion:
FRAMESHIFT MUTATION – a shift in the reading frame, which produces a non-functional protein
3Deletion and Insertion Mutations are usually caused by Replication Slippage

D.Exon Skipping – results from mutation at the spliced site

Splicing of an intron requires an essential signal, for example, “GT…….AG”. If the spliced acceptor
site AG is mutated, the splicing machinery will look for the next acceptor site. As a result, the exon
between two introns is also removed.

Exon 1 Exon 2 Exon 3

GT AG GT AG

Intron 1 Intron 2

A to C mutation

Exon 1 Exon 2 Exon 3

GT CG GT AG

Intron 1 Intron 2

Spliced Message:
Exon 1 Exon 3

Removed Introns:

Exon 2
GT CG GT AG

Intron 1 Intron 2
SPONTANEOUS MUTATION
- likely mutations that occur because of the following:

1.During DNA Replication

2.Insertion or Deletion during Replication Slippage
3.Tautomer Mispairing

INDUCED MUTATION
1are mutations that were acquired from outside (environmental factors).

Physical agents
2mutagens in the form of high energy radiation
 UV radiation – leads to formation of dimmers which can block DNA replication or interfere with
 base pairing.
Ex. Thymine Dimers

 X-rays – leads to single and double-stranded DNA breaks or may lead to formation of hydroxyl
radicals from water.

Chemical and Environmental mutagens

 Base Analogues
1have similar structures to the DNA bases which undergo tautomerism enabling to cause tautomer
mispairing
Example: 5-bromouracil

 Alkylating Agents
2adds a methyl or ethyl group to a base
3the largest class of potential mutagens present in man’s environment
Example: N-nitrosoamines (in cigarette smoke)
When N-nitrosoamine is in the liver, it is metabolized by liver enzymes to form alkylating agents which
can attack guanine. If alkylation occurs, an apurinic site is produced. During replication, an apurinic
site may be ignored resulting in a deletion in the daughter strand or a base selected at random and
place in the daughter strand.

 Deaminating Agents
4removes amino groups from a base
example: Sodium nitrite (used as preservative, color enhancer and color fixative in bacon, smoked
fish, tocino, etc.)
When ingested, NaNO2 is converted to nitrous acid in acidic conditions. HNO 2 removes functional
groups from Adenine, Guanine and Cytosine. Like deamination of adenine, will result in the formation
of hypoxanthine, a base analogue of guanine.

N
HN

N N
H

hypoxanthine

 Intercalating Agents
5contains a cyclic system that can interact with the bases of the DNA
6it physically binds to the bases by inserting itself between adjacent base pairs because of its planar
structure. This affects the opening of the DNA during replication or transcription.
Examples: Benzo-a-pyrene (found in cigarette smoke), benzene (an organic solvent), Aflatoxin (a
metabolic product of molds in peanuts, oils and grains).
 O
O

Benzopyrene

Aflatoxin

 Viral Agents
7some viruses contain oncogenes which can be activated once they are insert their DNA in the host’s
genome.
8When virus inserts their DNA into the host’s genome, the sequence of the bases of the host DNA
may be altered or certain destructive genes can be activated.