Session 6: DNA Repair & Cancer Flashcards
Describe how non-homologous end joining works?
- Double strand DNA break is recognised by proteins that bind to them
- more proteins are recruited that remove any potential damaged DNA components from the ends of the strands
- both protein-capped ends are brought together and DNA ligase is used to ligate ends back togther
What are the potential problems with non-homologous end joining?
- Short sequences of DNA are often lost from the broken ends prior to ligation so can cause a change in coding sequence and loss of function of genes in which break occurred
- Wrong ends may be joined together if there more than just 2 DNA ends close together
What are chromosomal translocations?
A translocation is a type of chromosomal abnormality in which a chromosome breaks & a portion of it re-attaches to a different chromosome
2 double-strand DNA breaks are needed on 2 chromosomes. A stretch of one chromosome translates to another chromosome
What are chromosomal inversions?
2 double-strand DNA breaks on the same chromosome, both breaks are repaired but the part in the middle is flipped over.
What type of repair are the genes involved in Xeroderma pigmentosa? How do you know this?
Nucleotide excision repair because UV radiation produces a thymine dimer.
List ways in which DNA can be damaged (6).
- UV light
- Metabolism
- Inflammation
- Exposure to carcinogens eg smoking
- Ionizing radiation
- Air pollution
Why are individuals with Xeroderma pigmentosa highly sensitive to sunlight?
Because damage to DNA is not repaired by the DNA excision pathway. Dimerisation of adjacent thymine base pairs
What are the 3 types of single-strand break repair?
- Base excision repair
- Nucleotide excision repair
- Mismatch repair
Explain how base pair excision repair works.
- Deamination converts cytosine (C) base into uracil (U)
- U is detected and removed leaving a baseless nucleotide
- The baseless nucleotide is removed, leaving a small hole in the DNA backbone
- The hole is filled with the right base by DNA polymerase & the gap is sealed by a ligase
Explain how nucleotide excision repair works.
- UV radiation produces a thymine dimer
- Dimer detected causing surrounding DNA to open and form a bubble
- Enzymes cut the damaged region out of the bubble
- DNA polymerase replaces the excised (cut out) DNA and a ligase seals the backbone
Explain how mismatch repair works.
- Mismatch is detected in newly synthesised DNA
- New DNA strand is cut and the mispaired nucleotide and neighbours are removed
- Missing patch is replaced with correct nucleotides by a DNA polymerase
- DNA ligase seals the gap in DNA backbone
What are the 3 types of double-strand break repair?
- Non-homologous end joining
- Homology-directed repair
- Holiday junction resolution
How does homology-directed repair work?
- A protein complex resects the DNA on either side of the break
- The protein complex then permits a heteroduplex to form, combining the broken 3’ single strand and an unaffected homologous dsDNA sequence
- Displacement loop moves along DNA making a complimentary strand to a 3’ single-strand template
- The newly synthesised DNA is captured by a 5’ single strand of the original template. Polymerase & ligases repair the break
What is intratumor heterogeneity? How does it lead to chemotherapy resistance?
Different cell types within a tumour
- Chemotherapy works well against all tumour subclones causing a reduction in size
- But chemotherapy may cause a subclone to mutate ad become resistant to chemo
- Subclone will start growing and increase tumour size
What is intertumour heterogeneity? How does it lead to chemotherapy resistance?
Differences between different tumours across different parts of the body
- Tumours are not homogenous (diff subclones exist within tumours)
- Chemo works well against all but 1 resistant subclone
- Killing off other subclones will reduce tumour size but chemo is not killing all of the tumour
- Resistant subclone will continue to proliferate & take over.
