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CAN > Maintenance of genome integrity > Flashcards

Maintenance of genome integrity Flashcards

1
Q

How can DNA be damaged?

A

Copying errors during replication
Spontaneous depurination
Exposure to environmental agents e.g. ionising radiation, UV, tobacco

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2
Q

What is alkylation?

A

The transfer of an alkyl group from one molecule to another. Has the potential to kill cells.

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3
Q

Describe the alkylation that occurs to produce 7-methyl-guanine due to the durg ethyl methane sulphonate.

A

The drug creates an abnormal purine that has been methylated. Guanine no longer pairs with cytosine but instead with thymine, due to the O6 alkyl group. This causes an overally transition in the base pairing. It creates a large distortion in DNA which prevents the cell from replicating and induces apoptosis.

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4
Q

What is the issue with O6 alkyl guanine mutation?

A

It increases susceptibility to cancer

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5
Q

What damage does UV radiation cause?

A

UV damage may occur as thymine dimers or photoproducts

or a break in the sugar-phosphate backbone

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6
Q

What is the problem with thymine dimers and what are they?

A

Two thymines covalently linked to from a cyclobutane ring, distorting DNA and causes difficult in replication. The thymines are not seen as two separate bases. This creates a gap that will be filled by a random base = mutagenic lesion

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7
Q

What type of damage can be fixed by reversal of damage?

A

UV induced dimers
O6 alkyl gunanine
Sugar phosphate backbone breaks

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8
Q

What is the mechanism behind reversal of damage?

A

Dimers fixed by MONOMERISATION where the bond of the ring is broken using visible light and photolyase.
Alkyl is removed by alkyl transferase
Backbone breaks are fixed by LIGATION

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9
Q

What type of damage can be fixed by base excision repair?

A

Spontaneous hydrolytic depurination of DNA
Deamination of cytosine
Formation of DNA adducts after exposure to reactive small metabolites

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10
Q

What is the mechanism behind base excision repair?

A

1) The altered DNA base is excised by DNA GLYCOSYLASE which breaks the sugar-base glycosyl bond.
2) The resulting abasic site is corrected by removing the apurinic sugar and phosphate and adding a new nucleotide via ligation.
It uses the other DNA strand as a template. Uses apurinic ENDONUCLEASE, DNA POLYMERASE and DNA LIGASE.

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11
Q

What is the use of nucleotide excision repair?

A

A non specific process which recognises distortions in dsDNA, rather than specific adducts. It removes and repairs the large adducts in an efficient and error free way.
Repairs UV damage (dimers and photoproducts)

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12
Q

What is the overall mechanism of nucleotide excision repair?

A

A ssDNA segment containing the damage is removed and the undamaged strand is used as a template to synthesise a complementing sequence to be ligated back into the DNA.

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13
Q

What enzymes are involved in nucleotide excision repair?

A

Endonucleases - remove
Exonucleases - cleaves from end
Polymerase - Creates new polynucleotides
Ligase - Puts strand together

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14
Q

What is a daughter strand gap repair?

A

It is a short term resolution until the thymine dimers can be removed by excision repair. Gaps are left opposite the dimers during repliction to allow them to repair on their own with time even if the dimers are still present.

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15
Q

What are the 9 proteins involved in nucleotide excision repair?

A

XPA - G

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16
Q

Which proteins recognise thymine dimer damage?

A

XPC and XPE

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17
Q

Which protein recognises photoproducts?

A

XPC

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18
Q

What does recognition by XPC result in?

A

Recruitment of XPA and TFIIH to verify the damage

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19
Q

Which proteins are contained within TFIIH?

A

XPB and XPD to unwind the DNA around the lesion

20
Q

Which proteins cleave the lesion?

A

XPF and XPG nucleases

21
Q

What enzymes are then involved in replacing the bases?

A

Polymerase and ligase

22
Q

What is xeroderma pigmentation?

A

An autosomal recessive disorder which causes patients to have extreme sensitivity to the sun and may develop tumours.

23
Q

How does a Pt with xeroderma pigmentation present histologically?

A

Fibroblast show increased sensitivity and a defect in nucleotide excision repair. Cells killed more easily by UV light.

24
Q

Why does xeroderma pigmentation increase the risk of skin cancer?

A

As nucleotide excision repair is impaired, the dimers cannot be removed from the DNA, causing mutations during replication due to incorrect base incorporation.

25
Q

How do specific syndromes arise from xeroderma pigmentation?

A

Dimers occur at random on the DNA but when the occur at specific genes they produce specific features e.g. PITCH1 gene = basal cell carcinoma

26
Q

What happens in a Pt with XP variants?

A

Cells are hypermutable by UV but are not deficient in excision repair or sensitive to killing. Cells are deficient in replication following UV exposure and in DNA polymerase which can normally replicate around photoproducts.

27
Q

What substance increases sensitivity to UV?

A

Caffeine.

28
Q

What is the involvement of BRCA genes in double stranded break repair?

A

BRCA1 is found in many repair proteins
BRCA2 mediates binding to Rad51
Both are involved in the cellular response to DNA damage.

29
Q

What does an increased sensitivity to gamma rays show?

A

Defect in ds break repair due to mutation is BRCA.

30
Q

How are ds breaks repaired?

A

Homologous recombination or non-homologous end joining

31
Q

Which is the most accurate form of DNA repair?

A

Homologous recombination

32
Q

What enzyme is vital for homologous recombination repair and why?

A

Rad51 provides catalytic activity by acting as a recombinase. It coats ssDNA to form a nucleoprotein filament that invades and pairs with homologous DNA to initiate strand exchange.

33
Q

What regulates Rad51?

A

BRCA2 determines the availability and activity of Rad51. BRCA2 interacts directly with BCR repeats to control the intracellular movement and function at the site of damage.

34
Q

What causes the release of Rad51?

A

Triggered by DNA damaged and released through phosphorylation of Rad51 itself or BRCA2.

35
Q

What is the role of BRCA1?

A

Interacts with and removes 53BP1 at the site of the ds break prior to homologous recombination.

36
Q

What is the function of 53BP1?

A

Links upstream signalling to indicate there is damage

37
Q

What happens during homologous recombination?

A

The homologous chromosome is used to repair the ds break by exchanging nucleotide sequences. Most commonly occurs during meiosis.

38
Q

What controls non-homologous end joining?

A

A normal cellular process of VDJ recombination in the formation of TCRs and antibodies. It is not under control of Rad51 or BRCA so is ERROR PRONE.

39
Q

What is the difference between the functions of BRCA 1 and 2 in DNA repair?

A

BRCA 1 links upstream signalling of damage through 53BP1 in recombination repair and is involved in cell cyle checkpoints.
BRCA 2 controls Rad51 recombinase in homologous recombination.

40
Q

Cells that are defective in homologous repair are usually sensitive to what type of treatment?

A

PARP inhibitors - Given to Pts with homologous repair deficient tumour cells to inhibit DNA repair through the base excision pathway to selectively kill cells that have lost the function of repair.

41
Q

How do PARP inhibitors work?

A

By preventing a single strand repair it will cause a ds break that cannot be repaired and will lead to cell death.

42
Q

What causes hereditary non polyposis colorectal cancer?

A

A mutation in the mismatch repair gene means that errors occur and results in the wrong size microsatellites. e.g. MLH1, MSH2, MSH6

43
Q

What type of damage does mismatch repair fix?

A

Repairs base-base mismatches and insertion deletion loops which arise due to polymerase slipping during replication.

44
Q

How does the slipping of DNA polymerase lead to damage?

A

The slip causes a gain or loss in repetitive DNA areas = microsatellite instability.

45
Q

Which types of genes have an increased risk of mutatuons in HNPcolorectal cancer?

A

Those with microsatellites in their coding region

46
Q

What is the mutator phenotype hypothesis?

A

Mismatch repair defects lead to mutations in other genes and the increased mutation rate is the cause of accelerated tumourgensis. It suggests that the mutator phenotype plays a role in tumour PROGRESSION rather than initiation.
Rapid mutations = rapid tumour growth

47
Q

What is microsatellite instability?

A

Frameshift mutations in many different genes, affecting the growth of cancers. The instability impairs mismatch repair. Can affect the mismatch repair genes themselves.

CAN (16 decks)

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