DNA Damage and Mutation

DNA Mutation

Any alteration to the genetic material that produces a heritable change in the nucleotide sequence

Forward mutation

A process that converts a wild-type to a mutant

Revertion mutation

Process that converts a mutant to a wild-type

Genome rearrangements mutation

Redistribution of genetic material between chromosomes, often arises from chromosome breakage

Changes in chromosome number

Usually arises from mistakes in chromosome segregation at cell division

Inversion mutation

The genomic sequence is reversed

Pyrimidines and purines

Pyrimidines = single ring

Purines = double ring

Silent or samesense

No effect on amino acid sequence

Missense

Results in an amino acid substitution

Nonsense

Changes an amino acid for a stop codon

Readthrough

Changes a stop codon to an amino acid

Mutagen

A chemical or physical agent that causes mutation

DNA damage

Chemical lesions from DNA

Depurination mutation

Glycosidic bind between the base and the sugar is cleaved by hydrolysis resulting in an apurinic or apyrimidic site

Deamination mutation

Amine groups on the rings of the bases are susceptible to spontaneous oxidation to aldehyde groups

• Deamination alters the pairing properties of the bases

Tautomeric shifts

Involves a transient change in the chemical structure of DNA bases, potentially causing them to potentially pair with incorrect bases

Endogenous oxidative damage

Can induce DNA damage by causing oxidative stress, where reactive oxygen species like free radicals attack DNA, altering its structure and leading to various lesions like oxidized bases and strand breaks

Damage limitation for endogenous oxidative damage

Catalases, peroxidases and superoxide dismutases minimize the accumulation of these two oxidants

Radiation indirect effects

Particle interacts with other molecules which then interact with the DNA

• Hydroxyl radicals generate damaged bases

• The production of clustered lesions can also lead to chain breaks

Radiation direct effects

Particle imparts its energy directly to the DNA molecule

• Breakage of bonds that hold the sugar phosphate backbone together

Chemical mutagens

Addition of methyl or ethyl groups to the aromatic rings can alter the pairing properties and so are often called miscoding lesions

DNA crosslinking

Certain chemicals are capable of covalently joining two bases in complementary strands to form an interstrand crosslink

• DNA crosslinks prevent separation of the two strands and hence block transcription and DNA replication

Intercalation agents

Some chemicals are capable of intercalating (slip between) the stacked DNA bases

• Intercalation can cause single nucleotide insertions and deletions and block replication and transcription