What are the causes of variation between human genomes?
- DNA repair mechanisms to contend with damage due to environmental agents
- DNA replication errors
- Homologous DNA recombination during meiosis (allelic and non-allelic)
- Retrotransposition (regions of DNA that can copy themselves and then reinsert into another area).
What is ‘damage’ to DNA?
physical change in the strucutre of DNA
What is mutagenesis?
A change in the base sequence
What are the two broad classifications of types of DNA damage?
Exogenous i.e. UV light
Endogenous i.e. cellular mechanisms
what can the results be from DNA damage
cell cycle arrest, DNA repair, apoptosis, transcirption
what are the types of DNA damage
- Base loss
- Base modification (adduct formation, dimerisation)
- Inter-strand X-links
- DNA-protein X-links
- Strand breaks (single or double strand breaks)
What are the main repair mechanisms of DNA damage, excluding double strand break repair?
- Base excision repair
a. Problem with base (i.e. adduct added to it), done by glycosylases - Nucleotide excision repair - corrects thymine dimers and other large chemical adducts
- Mismatch repair:
a. Two nucleotides are mismatched (i.e. A-c or T-G). Exonuclease is used to remove some of the strand and replace it so the opposing base is then correct
b. Enzyme looks for a GATC (irrespective of where the problem is i.e. it could be really LONG)
What are the two main double strand break repair mechanisms ?
- Non-homologous end joining: where you just put the ends ‘flapping’ back together again. Requires a large protein complex. Done at G0 and G1 phase of the cell cycle because the chromatin is highly condensed (no way of actually scanning for homologous sequence that can be used as a template [no checking]). This method is particularly prone to error
- Homologous recombination: dependent on synthesis phase (s), need to use intact sister chromatids to fix the break, single strand from the damaged DNA invades the undamaged homologous, which is used as a template for repair. May be associated with crossover and introduction of variation.
What are some physical and chemical causes of DNA damage?
- Physical factors: ionizing radiation, US radiation
- Chemical factors: human made chemicals (alkylating agents, hydrocarbons, tobacco), chemotherapy and other medical exposures
Describe xeroderma pigmentosum.
Acute susceptibility to UV light-induced skin cancer due to mutations in genes involved in nucleotide excision repair. There are three stages to the disease, ending with numerous skin malignancies
Describe Li-fraumeni syndrome
This is an autosomal dominant cancer predisposition syndrome, with half of the patients developing a cancer by 30 years old.
P53 is knocked out can’t respond to DNA and programmed cell death
Many tumours can occur (p53 involved in many cancers)
Advantage know they are susceptible to environmental carcinogens (i.e. diagnostic X-rays)
Describe Lynch syndrome
This is an autosomal dominant cancer predisposition syndrome caused by deficiencies in mismatch repair.
It predisposes patients to a few cancers, but particularly colorectal cancer.
This syndrome is also characterised by non-cancerous polyps developing in the colon
What is the usual damage done to DNA by alkylating agents?
A methyl group is added to a guanine, which is then able to pair with thymine, instead of cytosine
What was the result of Chernobyl on the thyroid? What was significant about the genetic mechanism of this?
Chernobyl irradiated iodine, causing a significant increase in the incidence of papillary thyroid cancer.
These cancers had a high rate of chromosomal rearrangements, that featured fusion genes - two genes fuse together where one is a regulator of growth/regulation, and has become unregulated. This causes these tumours to grow very rapidly.
