BC1001: Mutations: Types, Causes, and Repair Mechanisms

What can mutations affect?

Mutations can affect protein structure and function

Mutation

Permanent change to the nucleotide sequence in DNA

How do mutations arise?

(i) Mistakes made during DNA replication (ii) DNA damage from environmental agents (e.g., UV light, chemicals) (iii) Spontaneous hydrolytic reactions

Mistakes during DNA replication

A mutation may be introduced by misincorporation of a base in the first round of replication, becoming permanent in the second round

DNA damage from environmental agents

Nitrous acid

Changes cytosine to uracil, leads to a C

G to T

UV light

UV radiation links carbons 5 and 6 of each base ring to one another

Intercalating agents

Planar molecules (e.g., ethidium bromide) that insert between two adjacent base pairs, leading to insertion of an additional base

Spontaneous hydrolytic reactions

Depurination

Results in the deletion of a base without breaking the phosphodiester bond

Point mutation

Single base pair change or substitution

Missense mutation

Changes in DNA sequence lead to a different amino acid (e.g., TGG → TGT changes Trp to Cys)

Nonsense mutation

Change creates a stop codon in the coding region (e.g., TGG → TGA changes Trp to Stop)

Silent mutation

Change in coding region does not affect the amino acid (e.g., TAT → TAC both code for Tyr)

Insertions

Extra base pairs inserted into the DNA sequence

Deletions

A base pair is deleted from the DNA sequence, altering the codon and shifting the reading frame, leading to frameshift mutations

Nucleotide Excision Repair

A repair system that removes and replaces damaged DNA using the undamaged strand as a guide

Step 1 (Nucleotide Excision Repair)

Nuclease hydrolyzes two phosphodiester bonds, removing a single strand of DNA around the damage

Step 2 (Nucleotide Excision Repair)

DNA polymerase reads the template strand and incorporates complementary nucleotides

Step 3 (Nucleotide Excision Repair)

DNA ligase catalyzes the phosphodiester bond between the newly replaced DNA and the original strand

Xeroderma Pigmentosum (XP)

Rare recessive disease due to inability to repair DNA damage from UV light

caused by mutations in one of 7 genes involved in nucleotide excision repair

Symptoms of XP

Hypersensitivity to sunlight, Multiple pigmented (blackish) spots on the skin, Skin becomes wrinkled, dry, and old, Skin cancers develop

Treatment for XP

No cure

protection from UV exposure

Sickle Cell Anemia

Example of point mutation

AD

Autosomal dominant