What are the 3 types of DNA damage?
- Exposure to mutagens
- Oxidative damage
- Radiation
Give examples of genetic lesions that can occur in DNA after damage.
ds/ss DNA breaks, base changes, translocations, amplifications.
Give an example of internal damage.
ROS - mutation in cytochrome oxidase I causes accumulation.
What is Xeroderma Pigementosum?
Mutation in 1-7 genes involved in DNA repair, results in the inability to repair DNA after UV damage.
What are the 4 cellular consequences of DNA damage?
- Repair and return to normality
- Apoptosis
- Accumulation of mutations
- Senescence
What is Li-Fraumeni syndrome?
Have inactive p53 - very tumour prone.
What is the percentage of p53 mutations in Ovarian cancer?
47.8%
What structure does p53 form to act as a TF?
A homotetramer
Where are mutations commonly found in p53?
The DNA binding domain - often in arginine residues - alter ability of p53 to bind DNA.
What is another mutation in p53?
Can be structural alteration in the DBD e.g. R175H
What is the issue with having one mutant p53 allele?
p53 acts a tetramer and can bind p53 mutants, this reduces affinity for DNA.
What is the target sequence of p53?
PuPuPuCWWGPyPyPy
What are the 3 downstream effects p53?
- Arrest and repair
- Apoptosis
- Regulatory genes
What are the 3 pro-arrest genes that p53 targets?
- p21 (inhibits cell cycle progression and DNA replication by binding PCNA).
- MIR34A - inhibits expression of cyclin E1 and cdk4.
- 14-3-3 - binds to phosphorylated cdc25 (Ser225) and removes from nucleus.
What are the 2 pro-apoptotic genes that p53 targets?
- Bax - upregulates and downregulates Blc2 - allowing pores to form in mitochondria, activating the apoptosome.
- PTEN - removes phosphorylation on inositol, preventing Akt activation.
