Genome Stability & Cancer Flashcards
When does genomic instability most contribute to cancer
At the early stages where it is thought to contribute to cancer cells developing the hallmarks of cancer
How is oncogene induced senescence an example of the mutational stepwise progression of cancer
As oncogene sensecence is induced in the absence of co-transforming mutations that enable cells to evade the cell cycle checkpoints
What are the 2 complexes that can recognise/sense DNA Damage
Ku
MRN Complex
How many mutations occur a day
100,000
What type of DNA Damage is caused by the following and how is it repaired: Radio/Chemotherapy
DSBs
ATM, DNA-PKs
What type of DNA Damage is caused by the following and how is it repaired: UV Light
Bulky Adducts
XP, Polymerase
What type of DNA Damage is caused by the following and how is it repaired: Replication Errors
Insertions/Deletions
MLH1, MSH2
What type of DNA Damage is caused by the following and how is it repaired: Alkylating Agents
O6-Alkylguanine
AGT
What type of DNA Damage is caused by the following and how is it repaired: X-Rays
Single Strand Breaks
PARP
DDR Defects can lead to what human diseases
Cancer Immune deficience Neurodegenerative disroders Infertility Age-related diseases Clinical radio and chemosensitivity
What happens if DNA damage is too big
Get apoptosis or sensecence
What pathways are upregulated during the DDR
p53 and NFkB are induced by DNA damage
What % in the nucelus if Ku
2% of nuclear proteins
Describe the proteins that detect the changes in DNA in the G1, S and G2 phases of the DDR
G1: MRN and ATM, ATM Activates CHK2
S: ATR; activates CHK1
G2: ATM and ATR Required; activates CHK1 and CHK2
What is the point called telomeres become too short
Hayflicks limit –> telomeres become too short and expose DNA ends –> activates the DDR
How can cancer cells escape the oncogene sensecence
Suppress the DDR so that cancer cells are not arrested at cell cycle checkpoints
Name some common ways DNA damage arises
1) Mismatches during replication
2) Hydrolytic reactions and non-enzymatic methylations that generate thousands of DNA lesions per day
3) Reactive oxygen compounds as byproucts from oxidative respiration etc
When can HR occur
S and G2 phases
What do ATM and ATR do
They activate the CHK proteins AND also indue DNA-repair proteins transcriptionally or post-transcriptionally
Why does DDR functio in normal immune cells
Generates normal immune receptor diverstiy
1) V(D)J recombination
2) Class switching
3) Somatic hypermutation
Apart from immune diversity where does DDR FUnction normally
Production of gametes – trigered by Spo11 enzyme that causes DSBs ( It is related to a topoisomerase)
Telomere homestasis and ageing
Life cycles of pathogens –> where pathogens also possess DDR preoteins to mitigate cell damage
–> occasional mutational recombination allows new viruses to arise e.g. flu H5N1
Why might we want to inhibit the DDR in cancer treatments
Cytotoxic drugs work by inducing DNA damage –> if we inhibited DDR then this might enahnce the effectiveness of radiotherapy and chemotherapies! –> many cancer cells also lack an aspect of DDR so concept of synthetic lethality where if we inhibit them further it will affect these cells more
Which viral disease might the use of DDR inhibitor be beneficial in
HIV is reliant on host DDR proteins hence inhibiton of the DDR respnse in host cells could be a potential treatment.
What gene do the ATM and ATR pathways converge on
p53 –> pathways arrests cell cycle and allows DNA repair
What cancer was chromothripsis first detected in
CLL –> 42 genomic arrangements on the long arm of Chr 4 containing fragments from several other chromosomes
What are the three main features to characterise chromothripsis
1) Remarkable number of rearrangments in localised chromosomal regions
2) Low bimber of copy state genes across the region
3) Preservation of heterozygosity
These features all suggest that chromothripsis occurs during mitosis, wihin a relatively short period of time at an early stage of development
Why do micronuclei form
Due to anaphase-lagging chromosomes
Can DDR occur in micronuclei
YES BUT DOESNT EFFECTIVELY INDUCE THE G2/M CELL CYCLE CHECK POINT –> this means that during mitosis the chromosomes can be pulversied and then reincorpatted back into the main nucleus
What DDR Mutation can enhance micronuclei formation
RecQ mutations (encodes a DNA helicase) causes cancer predisposed Blooms syndrome!
What are cells usually deleted in if micronuclei form
p53 –> as generally micronuclei formaiton involved the generation of aneuploidy and aneuploidy cells are generally p53 deficient
