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Human Molecular B > Lecture 5 - DNA Damage > Flashcards

Lecture 5 - DNA Damage Flashcards

1
Q

How does damage to DNA occur?

A

Continuously

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2
Q

In humans approximatelt how many modifications occur per cell per day?

A

500,000 modifications

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3
Q

How is damage to DNA minimised?

A

Several different DNA repair systems

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4
Q

How does DNA damage occur?

A

1) cellular metabolism 2) UV light exposure 3) ionising radiation 4) chemical exposure 5) Replication errors

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5
Q

Cellular metabolism

A

Oxygen free radicals

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6
Q

Uv light exposure

A

UV-C, UV-B

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7
Q

Ionising radiation

A

Gamma Rays and X-rays

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8
Q

Chemical exposure

A

Certain hydrocarbons

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9
Q

Replication errors

A

Base mismatch, insertion/deletions

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10
Q

Endogenous Agents

A

Formed inside the cell by normal metabolic pathways

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11
Q

Exogenous agents

A

Come from the surrounding environment

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12
Q

What are some examples of single bases Changes?

A

Base alkylation Base deamination Base oxidation

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13
Q

Single bases changes

A

Affect the sequence of DNA but do not grossly distort the overall structure Does not affect the actual processes of transcription and replication

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14
Q

What does structural distortion provide?

A

Physical impediment to the processes of transcription or replication Adduct formation (e.g. benzo(a)pyrene) Non-ionising radiation eg. Photodjmerism by UV light

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15
Q

Healthy cell

A

Rate of DNA damage = rate of repair

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16
Q

Diseased cell

A

Rate of damage > Rate of repair

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17
Q

What are the DNA repair mechanisms?

A

Direct reversal Excision Repair ( 3 types ) Recombinatorial Repair ( 2 types ) Translesion Repair

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18
Q

What is direct reversal?

A

Rare Direct reversal or simple removal of the damage e.g. repair of Alkylated bases

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19
Q

What disrupts the appropriate pairing between nucleotides by alkylation (such as methylation) bases within DNA

A

Chemical mutagens

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20
Q

Where does alkylation take place?

A

Nitrogen and oxygen atoms external to the base ring systems Nitrogen atoms in the base ring systems except those linked to deoxyribose Non-bridging oxygen atoms in the phosphate groups

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21
Q

What is an example of mispairing?

A

06-methylguanine

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22
Q

What does deamination of methylated cytosine lead to ?

A

Change to thymidine

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23
Q

What happens if the methyl groups are not removed?

A

DNA replication of the mispair will lead to transition mutations

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24
Q

What is alkylation of O6-mythlguanine removed by?

A

O6-alkylguanine DNA alkyltransferase

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25
Q

In the alkylated bases, what does each domain of the active site containing residue consist of?

A

Cys 69 and Cys 321

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26
Q

Where does the N-terminal domain transfer an alkyl group from?

A

Phosphotriesters to Cys 69

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27
Q

What does the C-terminal domain transfer?

A

Alkyl group from either O6-alkylguanine or O4-alkylthymine to Cys 321

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28
Q

What are examples of excision repair?

A

Base Excision Repair (BER) Nucleotide Excision Repair (NER) Mismatch Excision Repair (MER)

29
Q

What is Base Excision Repair?

A

Recognises damage to single bases and either repairs the bases alone (short-patch Repair) or replaces 2-10 nucleotides (long-patch Repair)

30
Q

What is the base Excision repair triggered by?

A

Directly removing a damaged base from DNA

31
Q

What does the base removal trigger?

A

The removal and replacement of a single/stretch of nucleotides

32
Q

What does the DNA polymerase delta/epsilon pathway replace?

A

Long polynucleotide stretch

33
Q

What does the DNA polymerase beta pathway replace?

A

A short stretch

34
Q

Reactive Oxygen species - oxidation

A

Caused by superoxide and hydroxy radicals generated by cellular respiration 8-oxguanine can Base pair with cytosine or Adenine

35
Q

What kind of mutation does the unrepaired the 8-oxoG-A cause?

A

Transversion mutation

36
Q

What is deamination?

A

The removal of an amino group

37
Q

What does DNA repair enzymes recognise?

A

Uracil as an inappropriate Base in DNA and removes it

38
Q

What does DNA Glycosylases remove?

A

Bases from DNA by cleaning the bond to the deoxyribose (using H20)

39
Q

What do DNA glycosylases and AP lease recognise?

A

Damaged bases, flip it out of the helix and cleave the N-glycosidic bind generating an apurinic or apyrimodinic site (abasic site)

40
Q

What does AP endonuclease do?

A

Cleaves the DNA backbone 5’ of the AP site to produce a buck and create a 5’-deoxyribose phosphate and a free 3’-OH end

41
Q

What is the short patch repair?

A

DNA polymerase Beta adds a nucleotide to the 3’-OH and DNA ligase seals the end

42
Q

What is the Long Patch Repair?

A

DNA polymerase delta or epsilon act with clamp loader (RFC) and sliding clamp (PCNA) adds 2-8 nucleotides to the 3’-OH generating a flap which is removed by Flap endonuclease and sealed by DNA ligase

43
Q

What is Nucleotide Excision Repair?

A

Recognises bulky lesions/adducts In DNA (UV-induced pyramidine dimers) Oligonucleotide is excised bearing the lesion and is replaced with newly synthesised DNA

44
Q

What are two major sub pathways of NER?

A

Global genome repair - repairs damage anywhere in the genome Transcription-coupled repair (TC-NER) - repairs damage in the transcribed strand of active genes

45
Q

What is an example of Adduct formation?

A

Polycyclic aromatic hydrocarbons

46
Q

UV-A

A

320-400 - majority of UV light reaching earth does little DNA damage

47
Q

UV-B

A

295-320nm - 10% of UV light reaching earth responsible for most of DNA damage in skin

48
Q

UV-C

A

100-295nm - includes wavelength maximum of DNA Little reaches Earth’s surface due to ozone layer

49
Q

What does cyclobutane pyrimidine dimer (CPD) account for?

A

75% of UV induced damage

50
Q

What happens in photodimerism?

A

DNA helix is distorted Transcription may be blocked Cyclobutane pyrimidine dimers produce a kink in DNA

51
Q

What does several human diseases involve?

A

Inherited defects in genes

52
Q

What are some examples of inherited effects in genes?

A

Xeroderma pigmentosum Cockayne syndrome PIBIDS

53
Q

What are common characteristics of all three syndromes?

A

Increased sensitivity to sunlight

54
Q

What are some examples of damage recognition ?

A

XPC and hHR238 detects helix distortion and stabilises the bend, recruit transcription factor TFIIH XPB and XPD subunits of TFIIH are helicases which use ATP to unwind DNA and generate a 20bp open “bubble” structure XPD subunits detects the chemically modified Base

55
Q

What is RPA?

A

Single stranded DNA binding protein

56
Q

What forms the “preincision” complex?

A

RPA and XPA and then XPG

57
Q

What are advantages of targeting of DNA repair enzymes to actively transcribing genes?

A

Active genes are more loosely packed and may be more vulnerable to DNA damage Transcription may make DNA more susceptible to damage
DNA regions that contain active genes are more likely to be important for survival than non-transcribed regions

58
Q

What is Mismatch Repair?

A

Corrects distortions introduces by mispaired bases and short deletions or insertions that appear in DNA shortly after replication

59
Q

What does Mismatch Repair require?

A

ATP

60
Q

What is Mismatch Repair specific to?

A

Newly synthesised (daughter) DNA strand

61
Q

What are the 3 proteins found in prokaryote it Mismatch Repair?

A

MutL,MutH, MutS

62
Q

What do the proteins detect?

A

Mistmatch and direct it’s removal from the newly made strand

63
Q

What are the eukaryotic homologs?

A

Msh2 (MutS), Msh3, and 6 are specificity factors

64
Q

What is a key characteristic of MutH?

A

Distinguish between parental strand and the daughter strand

65
Q

What does DNA polymerase III synthesise?

A

New strand directed by the template strand - DNA ligase seals the ends

66
Q

What is Homologous recombination?

A

Repair of DNA double strand break

67
Q

Where does the homologous recombination happen?

A

S and G2 phases - uses sister chromatid as a template - doesn’t create mutations

68
Q

What is Non-homologous end joining?

A

Sticks the ends of DNA together - the process leads to loss of some of the DNA around the break and therefore to mutations

Human Molecular B (13 decks)

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