DNA repair Flashcards
What is depurination?
- Loss of urine bases (adenine and guanine)
- Occurs spontaneously thousands of times per day
what nucleotide is most commonly affected by deamination (loss of amine group)?
Cytosine
What does cytidine become after deamination?
Uracil
What do free radiacls or radation damage on the nucleotide?
Base rings
What are possible damage will free radicals so to the base rings?
- Oxidative damage
- Methylation
- Hydrolysis
What are the single strand repair mechanisms?
- Base excision
- NT excision
- Mismatch repair
What are the double strand repair mechanisms?
- Homologous end joining
- Non-homologous end joining
What is the pathway for damaged DNA repair called?
Base excision repair
- Recognises specific base errors
What is the function of a DNA glycosylase?
Remove damaged bases
- Creates a baseless NT
What can a baseless NT be known as?
- Apurinic or apyrimidic
What is the function of an AP endonuclease?
- Recognises NTs w/o a base
- Attacks 5’ phosphate end of DNA strand
- Nicks damaged DNA upstream of AP site
- Create a 3’-OH end adjacent to the AP site
What is the function of an AP lyase?
- Some DNA glycosylases also possess AP lyase activity
- Attack the 3’ hydroxyl end of ribose sugar
What end of the sugar does AP endonuclease attack?
5’ end
What end of the sugar does AP lyase attack?
3’ end
What are the 5 enzymes involved in base excision repair?
- DNA glycosylase
- AP endonuclease
- AP lyase
- DNA polymerase
- DNA ligase
What kind of DNA damage does nucleotide excision repair remove?
Bulky DNA damage
- Multiple bases
- Often pyramidine dimers
- Commonly caused by UV radiation
When does nucleotide excision repair occur?
G1 phase (prior to DNA synthesis)
What enzymes remove multiple nucleotides in nucleotide excision repair?
Endonucleases
What strange link can UV light cause in the DNA?
Pyramidine dimer
What skin condition is caused by defective nucleotide excision repair?
Xeroderma Pigmentosum
What does Xeroderma Pigmentosum increase the risk of?
Skin cancer
What does mismatch repair recognise?
- Incorrectly plased bases/NTs
- Not damaged DNA
- Occurs when proofreading misses errors
- Newly synthesised strand compared to template
- NT errors removed and resealed
When does Mismatch repair occur?
S/G2 phase (after DNA synthesis)
What is mismatch repair important for maintaining?
Microsatelite stability
- DNA repeating segments
- Repairs DNA slippage
What is HNPCC (Lynch syndrome) due to a mutation in?
Germline mutation of DNA mismatch repair genes -> microsatellite instability
- 90% - MLH1 and MSH2 mutations
What is double strand damage commonly due to?
Exogenous damage
- Ionising radiation
- Radiation therapy
What does Homologous end joining use as a template to repair double strand breakage?
Sister chromosome template
What enzymes does non-homologous end joining use to re-join broken ends of DNA?
- DNA pol gamma and mu re-extends ends of broken DNA
- Many other enzymes
Why is non-homologous end-joining more error-prone?
No template used (non-homologous)
What type of enzymes are thought to cause Fanconi anemia?
DNA repair enzymes
- Hypersensitivity to DNA damage
- Cells vulnerable to DNA strand cross-links
- Also impaired Non-homologous end-joining
What is fanconi anemia?
Inherited aplastic anemia
- More than 13 genetic abnormaloties identified
What process is defective in ataxia telangiectasia?
Defective Nonhomologous end joining defective
What gene is defective in ataxia telangiectasia?
Where is it located?
ATM gene on chromosome 11
What type of radiation are those with ataxia telangiectasia vulnerable to?
Ionising
What systems are affected in ataxia telangiectasia?
- CNS
- Skin
- Immune system
What are the symptoms of ataxia telangiectasia?
- Healthy for 1st year
- Walking at normal age but slow development
- Motor coordination gets worse and by 10 years old most in wheelchairs
- Recurrent sinus/resp infections
- Telangiectasia (skin)
- High risk of cancer
