DNA Mutagenesis: Mechanisms & Biological Relevance Flashcards
DNA mutation
Change in nucleotide sequence or rearrangement of genetic material
Heritable mutations
- Organisms (parental germline)
- Viruses
- Can drive evolution
Acquired mutations
Somatic cells (so not present in all cells of body) -Can lead to cancer
Types of mutation
- Silent
- Missense
- Nonsense
- Frameshift
- Gross change
Mutations arise from
1) Misrepair of DNA damage
2) Spontaneous events
Exogeneous sources of DNA damage
- Ionising radiation
- Alkylating agents
- UV light
- Anti-cancer agents
- Free radicals
Endogeneous sources of DNA damage
- Free radicals
- Myosis
Types of DNA base damage
- Mismatch
- Base modification
- Abasic site
- Bulky adduct
- Interstrand crosslink
Types of DNA backbone damage
- Single strand break
- Double strand break
Most common indirect DNA damage
Radiolysis of water
H2O -> free radicals
Free radical
Highly reactive atom or molecule with single unpaired electron
Effects of single-strand break
Little effect, relatively simple to fix
Effects of double-strand break
- very difficult to fix
- Genotoxic: misrepair can cause gross structural changes
- Cytotoxic: no repair can be cytotoxic
Intercalating agents
- Add or delete single nucleotide at replication
- Induce frameshift mutations
Alkylating agents
- Very powerful mutagens
- Addition of alkyl group to DNA base
- Induces mispairing at replication
- Base substitution
Result of replication fork slippage of newly synthesised strand
New strand has an extra nucleotide
Result of replication fork slippage of template strand
New strand is missing a nucleotide
Allele
Alternative form of the same gene
SNP
Single nucleotide polymorphism (single base change in a particular form of a gene)
Anonymous SNP
No known effect on gene
Non-coding SNP
Outside gene
Coding SNP
- Within Gene
- Can be synonymous (encode same aa as original) or non-synonymous (change aa sequence)
CNV
‘Copy number variations’ (duplicates of same DNA segment)
Achrondoplasia
Disorder of bone growth that causes the most common type of dwarfism
Allosome
Sex chromosome
Autosome
Chromosome that is not an autosome
Cause of Huntington’s Disease
Gene has CAG repeats (polyglutamine)
-Normal gene, 6-39 repeats
-Disease gene, 35-121 repeats
Causes aggregates to form
Intra-tumour heterogeneity
The observation that different tumour cells can show distinct morphological and phenotypic profiles within a tumour mass
Hypervariable region
A region of a genome that is made up of a variable number of repeated sequences and is diagnostic for an individual
Ames test
Widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a biological assay to assess the mutagenic potential of chemical compounds
Reversion (mutation) frequency
Number of revertant colonies per total number of cells plated
Mutation rate
Number of mutations per generation
DNA damage from environment & normal metabolism
1x10^6 molecular lesions per cell per day
DNA damage response: overview
Sensor proteins -> transducer proteins -> Mediators/effectors -> DNA repair OR cell cycle checkpoints/senescence/apoptosis
Senescence
Temporary arrest (loss of a cell’s power of division and growth)
Apoptosis
Cell death
Cell cycle checkpoint
Different stages during mitosis in which temporary arrest takes place (until DNA damage is repaired)
