L3 - Early molecular events in development of cancer Flashcards
What is the fidelity of DNA repair?
Extremely high but each cell experiences thousands of DNA lesions per day
What are 3 causes of a mutation being allowed through repair?
- repair is not 100% effective and gets less precise with age
- Can be compromised by mutation
- Can be overwhelmed by number of damaged sites (massive carcinogen exposure)
What is needed other than a mutation to cause cancer?
Programmed cell death must also be disabled by mutation
How many errors does DNA polymerase 1 make and what does proofreading change this to?
1 in 10^5
Proofreading to 1 in 10^7
What does the Kaplin Mayer plot show?
Survival of a population of mice over 12 months.
WT survives 100%
Double mutation in proofreading subunit ends at 35%
How does the mismatch repair system know what the right sequence is?
Does it during replication and uses the okazaki fragments to detect the correct sequence
How does the mismatch repair system work?
- hMSH2 and hMLH1 scans new DNA for nicks
2. Remove strand with error then resynthesised
What cancer has mutations in the mismatch repair system?
Hereditary nonpolyposis colon cancer
What is the mutation of mismatch repair in the TGFb receptor and what does it cause?
2 more As added to sequence
Truncated receptor protein
How was it shown that the loss of MLH1 is early in the development of cancer?
Stained for MLH1 in endometrial tissue.
Showed cells that were not in the tumour had no MLH1 too.
How can pyrimidines damaged by UV light sometimes be repaired wrongly?
If they are not repaired in time the cell uses ‘error prone’ DNA polymerase to replicate past the lesion.
This can sometimes incorporate the wrong base fixing the mutation
Of 15000 cancers of the p53 gene in lung tumours ….. how many were caused by G-T transitions?
15% of total
In mutations of p53 gene in lung cancers how did smoking change the amount of G-T transitions? What does this mean?
From 21% in non smokers to 33% in smokers
Type of mutation provides clues about mutagenic agent
What can you take from the locations of common mutations in cancers?
Clues about the functional sites of the protein
What does melanin do?
Forms a cap on the top of skin cells protecting again UV damage
