Genome Stability & Cancer

Question 1

When does genomic instability most contribute to cancer

Answer 1

At the early stages where it is thought to contribute to cancer cells developing the hallmarks of cancer

Question 2

How is oncogene induced senescence an example of the mutational stepwise progression of cancer

Answer 2

As oncogene sensecence is induced in the absence of co-transforming mutations that enable cells to evade the cell cycle checkpoints

Question 3

What are the 2 complexes that can recognise/sense DNA Damage

Answer 3

Ku

MRN Complex

Question 4

How many mutations occur a day

Answer 4

100,000

Question 5

What type of DNA Damage is caused by the following and how is it repaired: Radio/Chemotherapy

Answer 5

DSBs

ATM, DNA-PKs

Question 6

What type of DNA Damage is caused by the following and how is it repaired: UV Light

Answer 6

Bulky Adducts

XP, Polymerase

Question 7

What type of DNA Damage is caused by the following and how is it repaired: Replication Errors

Answer 7

Insertions/Deletions

MLH1, MSH2

Question 8

What type of DNA Damage is caused by the following and how is it repaired: Alkylating Agents

Answer 8

O6-Alkylguanine

AGT

Question 9

What type of DNA Damage is caused by the following and how is it repaired: X-Rays

Answer 9

Single Strand Breaks

PARP

Question 10

DDR Defects can lead to what human diseases

Answer 10

Cancer
Immune deficience
Neurodegenerative disroders
Infertility
Age-related diseases
Clinical radio and chemosensitivity

Question 11

What happens if DNA damage is too big

Answer 11

Get apoptosis or sensecence

Question 12

What pathways are upregulated during the DDR

Answer 12

p53 and NFkB are induced by DNA damage

Question 13

What % in the nucelus if Ku

Answer 13

2% of nuclear proteins

Question 14

Describe the proteins that detect the changes in DNA in the G1, S and G2 phases of the DDR

Answer 14

G1: MRN and ATM, ATM Activates CHK2
S: ATR; activates CHK1
G2: ATM and ATR Required; activates CHK1 and CHK2

Question 15

What is the point called telomeres become too short

Answer 15

Hayflicks limit –> telomeres become too short and expose DNA ends –> activates the DDR

Question 16

How can cancer cells escape the oncogene sensecence

Answer 16

Suppress the DDR so that cancer cells are not arrested at cell cycle checkpoints

Question 17

Name some common ways DNA damage arises

Answer 17

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

Question 18

When can HR occur

Answer 18

S and G2 phases

Question 19

What do ATM and ATR do

Answer 19

They activate the CHK proteins AND also indue DNA-repair proteins transcriptionally or post-transcriptionally

Question 20

Why does DDR functio in normal immune cells

Answer 20

Generates normal immune receptor diverstiy

1) V(D)J recombination
2) Class switching
3) Somatic hypermutation

Question 21

Apart from immune diversity where does DDR FUnction normally

Answer 21

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

Question 22

Why might we want to inhibit the DDR in cancer treatments

Answer 22

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

Question 23

Which viral disease might the use of DDR inhibitor be beneficial in

Answer 23

HIV is reliant on host DDR proteins hence inhibiton of the DDR respnse in host cells could be a potential treatment.

Question 24

What gene do the ATM and ATR pathways converge on

Answer 24

p53 –> pathways arrests cell cycle and allows DNA repair

Question 25

What cancer was chromothripsis first detected in

Answer 25

CLL –> 42 genomic arrangements on the long arm of Chr 4 containing fragments from several other chromosomes

Question 26

What are the three main features to characterise chromothripsis

Answer 26

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

Question 27

Why do micronuclei form

Answer 27

Due to anaphase-lagging chromosomes

Question 28

Can DDR occur in micronuclei

Answer 28

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

Question 29

What DDR Mutation can enhance micronuclei formation

Answer 29

RecQ mutations (encodes a DNA helicase) causes cancer predisposed Blooms syndrome!

Question 30

What are cells usually deleted in if micronuclei form

Answer 30

p53 –> as generally micronuclei formaiton involved the generation of aneuploidy and aneuploidy cells are generally p53 deficient