DNA Repair and Cancer Part 2 Flashcards
What happens if DNA damage is persistent or too high
If DNA damage is persistent or too high
then senescence or apoptosis will occur
Ideal scenario: repair DNA after insult
What is senescence
loss of a cell’s power of division and growth
What is apoptosis
the death of cells which occurs as a normal and controlled part of an organism’s growth or development.
How many check points are there is the cell cycle
Where do they take place
What does each other check for
There are three cell checkpoints
- G1- checkpoint
(checks whether environment is favourable)
- G2- checkpoint
(checks if all DNA is replicated & if damaged DNA is repaired)
- Checkpoint in mitosis
(Checks if chromosomes are properly attached to the spindle fibres)
What does the G2 checkpoint allow for
Checkpoint in G2 allows temporary arrest to repair DNA
What are the types of single strand break repair
Base excision repair
Nucleotide excision repair
Mismatch repair
What is Base excision repair
Deamination converts a cytosine base into a uracil
The uracil is detected and removed, leaving a base-less nucleotide
The base-less nucleotide is removed, leaving a small hole in the DNA backbone
The hole is filled with the right base pair by a DNA polymerase and the gap is sealed using a ligase
What is Nucleotide Excision repair
UV Radiation produces a thymine dimer
Once the dimer has been detected, the surrounding DNA is opened to form a bubble
Enzymes cut the damaged region out of the bubble
A DNA polymerase replaces the excised (cut of) DNA, and ligase seals the backbone
What is Mismatch repair
A mismatch is detected in newly synthesised DNA
The new DNA strand is cut and the mispaired nucleotide and its neighbours are removed
The missing patch is replaced with correct nucleotide by a DNA polymerase
A DNA Ligase seals the gap in the DNA backbone
What are the types of Double Strand break repair
Non-homologous end joining
Homology-directed repair
What is Non-homologous end joining
The broken ends are bound by Ku70/80 proteins
A complex of other proteins is bound and it trims of base pairs around the breakage
(DNA-PKcs complex is recruited, followed by Artemis and
MRN – resection (trimming of excess bp) occurs)
DNA ligase repairs the break
The new DNA may not be an exact copy of the original piece
Some base pairs may be missing which can lead to different consequences for different proteins
What is Homology-directed repair
The DNA either side of the break is resected by a protein
complex that includes ATM and MRN
A second complex called The Rad51 then permits a heteroduplex to form (pairing up with another copy of the gene found in the genome)
– combining the 3’ single strand and a homologous dsDNA sequence
A D-loop, or displacement loop moves along the DNA,
making a complementary strand to the 3’ single strand
template
The newly synthesised DNA is captured by the 5’ single
strand of the original template. Polymerase and ligases
repair the break
(Two copies of each gene in the genome
If only one is mutated, other can be used as a template)
Mutations in DNA repair genes can lead to cancer
Is it a multi-step process
What are the steps to cancer
There are multiple steps of a cell mutation till cell becomes cancerous.
Normal to
Pre-malignant to
Malignant
MULTIPLE Mutations accumulate over time until a threshold is passed and cancer is triggered.
What is Lynch syndrome
Lynch syndrome caused by defective mismatch repair
Also called Hereditary nonpolyposis colorectal cancer
Caused by mutations in mismatch repair genes: MLH1, MLH2, MSH6, PMS2
Autosomal dominant inheritance
(One parent can pass this on to their offspring)
High risk of colorectal, endometrial, gastric
and ovarian cancer
Treated by surgery in many cases
What is Intertumoral and intratumor heterogeneity difference
-Intra-tumor heterogeneity,
(different cell types with in a tumor)
-Inter-tumor heterogeneity,
(between different tumour)
