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Flashcards in DNA Damage Repar Deck (41)
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1
Q

What are 3 cellular responses to DNA damage?

A

Repair
Apoptosis
Cell cycle arrest

2
Q

Whats p53, which two things is it particularly important for? What happens when it mutates?

A

Effector in DNA damage repair, particularly important for senescence (cell cycle arrest) and apoptosis) - mutated in many cancers

3
Q

What are ATM ATR and DNA-PK?

A

Transducers - all kinases involved in DNA damage response that can phosphorylate etc downstream for either senescence, apoptosis, DNA repair.

4
Q

What happens when DNA damage is found? Starting with sensor…

A

Proteins sense DNA damage, signal to transducers to phosphorylate downstream to signal effectors to elicit a cellular response e.g. apoptosis, senescence or repair

5
Q

Why do you have cell cycle check points? What would happen if you didnt and a cell underwent mitosis?

A

Temporary arrest provides time for DNA damage to be repaired. If you didn’t and mitosis occurred, at metaphase you could either have a situation where two chromosomes can’t be pulled apart e.g. if crosslinked, or DNA may break during anaphase.

6
Q

How many check points are there? What is G1 G2 check point for? What is M for?

A

Check OK to progress to replication all DNA present Check DNA has been replicated before mitosis. Are chromosomes attached to spindle?

7
Q

When would you be most likely to get Senescence and apoptosis following DNA damage?

A

If there is a lot of DNA damage or damage persists for a long time

8
Q

What is senescence

A

Cell there but can never reenter cell cycle.

9
Q

Why don’t you want a cell with DNA damage to keep dividing?

A

Prone to cancer

10
Q

3 stages of BER? Give an example of when BER can be used?

A

Enzyme removes base
Enzyme repairs where base was
Enzyme fixes break that was formed

e.g. of a base that has been deaminated

11
Q

Which is the most common form of DNA damage that is implicated in cancers?

A

DSBs

12
Q

What is the difference between BER, mismatch repair and NER?

A

BER - replaces base - any point in cell cycle
Mismatch - switches base soon after DNA replication error (e.g. error in exonuclease function of DNA polymerase).
NER - replaces small section of DNA and bases around it, polymerases replace

13
Q

What 2 types of DSB repair are there? One type has 3 subtypes, what are they? Which of the two types is best and why?

A

Non homology directed repair

Homology directed repair

i) Simple annealing
ii) Synthesis dependant
iii) DSB repair - synthesis dependant and doesn’t lose DNA

Homology directed repair better as if done properly less prone to error.

14
Q

What happens in non-homology directed repair(3)?

note: there are 5 major factors/enzymes to remember

A
  • Protein complex Ku70/80 recognises broken ends and brings in other factors
  • Factors brought in that bring the ends together and DNA-Pkcs process them to remove lesions (can lose DNA)
  • Ligate ends - DNA ligase IV, XLF, XRCC4
15
Q

Which is the easiest way to DSB repair? What is the disadvantage?

A

Non homology directed

Error prone

16
Q

What happens during simple annealing homology directed repair (1) . What is the advantage? disadvantage?

A

1) Uses complementary sequences on 2 single strand DNAs to bind together

Error free

Causes deletions (the overhang on each single strand).

17
Q

What happens during synthesis dependant Homology directed repair (2)? When is it best done and why? Why is this better than single strand annealing?

A

1) Uses other undamaged chromosome as a template
2) Requires DNA polymerase to copy other chromosome

Best at DNA replication as can use identical copy of DNA strand rather than opposite maternal/paternal copy which could have different alleles.

Better than single strand because no loss of genetic information

18
Q

What happens during DSB Repair (Holliday Junction) (4)? Where else do see this kind of recombination?

A

1) Use other chromosome as a template
2) Both strands replicate with DNA polymerase - D-loop formation
3) DNA interlinked = 4 way Holliday Junction
4) 2 ways you can split chromosomes, either to give you 2 original chromosomes with the copied regions, or can cause cross-over.

Happens in meiosis.

19
Q

Define cancer

A

Uncontrolled cell growth

20
Q

What are 5 important proteins/substances used for non-homology directed repair

A
Ku70/80
DNA-PKcs
Ligase IV
IXF
XRCC4
21
Q

Which two types of homologous DNA repair require DNA polymerase?

A

Synthesis dependent and DSB repair (Holliday Junction)

22
Q

What can cause nucleotide disincorporation?

A

Defect in exonuclease function of DNA polymerase

23
Q

How can a defect in BER lead to a SSB persisting? What could happen if a SSB persists at DNA replication? What disease is this implicated in?

A

Defect in BER could prevent ligation back together of a strand that has been broken to remove nucleotide misincorporation. If this single strand break persists until DNA replication, when the strand is replicated it will become a DSB and break away. Implicated in cancers - risk of genomic instability

24
Q

What does DNA damage repair prevent?

A

Genomic instability and cancer

25
Q

What is it called where thousands of clustered chromosomal rearrangements occur in a single event? When is it seen?

A

Chromothripsis, can be seen in early tumour development

26
Q

Give syndrome and therefore cancer arises from a defect in mismatch repair? Is this germline or somatic mutation in a gene?

A

Lynch Syndrome
Colorectal Cancer
Germline

27
Q

DNA replication stress and DNA damage can both cause ______

A

Cancer

28
Q

Whats the biggest risk factor for cancer and why?

A

Age due to mutation and accumulation (added mutation over time due to DNA replication stress and DNA damage)

29
Q

Whats Werner Syndrome and what causes it . Recessive or dominant?

A

Premature ageing due to Helices problem - DNA replication stress = ageing. Recessive

30
Q

A problem with mismatch repair could cause what 4 mutations?

A

A-G mismatch
T-C mismatch
Insertion
Deletion

31
Q

A problem with BER repair could cause what 4 mutations?

A

Uracil accidentally in DNA
8-Oxyguanine mutations
SSBs
Abasic site

32
Q

A problem with NER repair could cause what 2 mutations?

A

Bulky adducts

Pyrimidine dimers

33
Q

A problem with Homology/recombinant DNA repair could cause what 2 mutations?

A

DSBs

Interstrand linkages

34
Q

What is crucial to locate DNA damage? Name one

A

Sensors - DNA-PKs

35
Q

what to ATM ATR and DNA-PKcs do?

A

Kinases phosphorylate downstream to cause either cell cycle arrest (and repair), senescence or apoptosis

36
Q

what is p53 an example of?

A

An effector protein - acts especially in apoptosis/senescence

37
Q

Name 4 things a transducer can do to downstream targets (1 is phosphorylation)

A

2) Ubiquitination
3) Sumoylation
4) Acetylation

38
Q

5 enzymes used in BER

A
Glycosylase
Endonuclease
Deoxyribophosphodiesterase
DNA polymerase
Ligase
39
Q

4 enzymes used in mismatch

A

Endonuclease
Exonuclease
DNA Polymerase
Ligase

40
Q

Whats tumour heterogeneity and what’s it’s affect on treatment

A

Subclones of cells within a tumour. Some clones may have mutated and become resistant to treatment, leads to a tumour with different cell types that is able to proliferate.

41
Q

State a problem with current cancer treatments

A

Cause DNA damage so promote tumour evolution and treatment resistance.