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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
In the alkylated bases, what does each domain of the active site containing residue consist of?
Cys 69 and Cys 321
26
Where does the N-terminal domain transfer an alkyl group from?
Phosphotriesters to Cys 69
27
What does the C-terminal domain transfer?
Alkyl group from either O6-alkylguanine or O4-alkylthymine to Cys 321
28
What are examples of excision repair?
Base Excision Repair (BER) Nucleotide Excision Repair (NER) Mismatch Excision Repair (MER)
29
What is Base Excision Repair?
Recognises damage to single bases and either repairs the bases alone (short-patch Repair) or replaces 2-10 nucleotides (long-patch Repair)
30
What is the base Excision repair triggered by?
Directly removing a damaged base from DNA
31
What does the base removal trigger?
The removal and replacement of a single/stretch of nucleotides
32
What does the DNA polymerase delta/epsilon pathway replace?
Long polynucleotide stretch
33
What does the DNA polymerase beta pathway replace?
A short stretch
34
Reactive Oxygen species - oxidation
Caused by superoxide and hydroxy radicals generated by cellular respiration 8-oxguanine can Base pair with cytosine or Adenine
35
What kind of mutation does the unrepaired the 8-oxoG-A cause?
Transversion mutation
36
What is deamination?
The removal of an amino group
37
What does DNA repair enzymes recognise?
Uracil as an inappropriate Base in DNA and removes it
38
What does DNA Glycosylases remove?
Bases from DNA by cleaning the bond to the deoxyribose (using H20)
39
What do DNA glycosylases and AP lease recognise?
Damaged bases, flip it out of the helix and cleave the N-glycosidic bind generating an apurinic or apyrimodinic site (abasic site)
40
What does AP endonuclease do?
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
What is the short patch repair?
DNA polymerase Beta adds a nucleotide to the 3’-OH and DNA ligase seals the end
42
What is the Long Patch Repair?
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
What is Nucleotide Excision Repair?
Recognises bulky lesions/adducts In DNA (UV-induced pyramidine dimers) Oligonucleotide is excised bearing the lesion and is replaced with newly synthesised DNA
44
What are two major sub pathways of NER?
Global genome repair - repairs damage anywhere in the genome Transcription-coupled repair (TC-NER) - repairs damage in the transcribed strand of active genes
45
What is an example of Adduct formation?
Polycyclic aromatic hydrocarbons
46
UV-A
320-400 - majority of UV light reaching earth does little DNA damage
47
UV-B
295-320nm - 10% of UV light reaching earth responsible for most of DNA damage in skin
48
UV-C
100-295nm - includes wavelength maximum of DNA Little reaches Earth’s surface due to ozone layer
49
What does cyclobutane pyrimidine dimer (CPD) account for?
75% of UV induced damage
50
What happens in photodimerism?
DNA helix is distorted Transcription may be blocked Cyclobutane pyrimidine dimers produce a kink in DNA
51
What does several human diseases involve?
Inherited defects in genes
52
What are some examples of inherited effects in genes?
Xeroderma pigmentosum Cockayne syndrome PIBIDS
53
What are common characteristics of all three syndromes?
Increased sensitivity to sunlight
54
What are some examples of damage recognition ?
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
What is RPA?
Single stranded DNA binding protein
56
What forms the “preincision” complex?
RPA and XPA and then XPG
57
What are advantages of targeting of DNA repair enzymes to actively transcribing genes?
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
What is Mismatch Repair?
Corrects distortions introduces by mispaired bases and short deletions or insertions that appear in DNA shortly after replication
59
What does Mismatch Repair require?
ATP
60
What is Mismatch Repair specific to?
Newly synthesised (daughter) DNA strand
61
What are the 3 proteins found in prokaryote it Mismatch Repair?
MutL,MutH, MutS
62
What do the proteins detect?
Mistmatch and direct it’s removal from the newly made strand
63
What are the eukaryotic homologs?
Msh2 (MutS), Msh3, and 6 are specificity factors
64
What is a key characteristic of MutH?
Distinguish between parental strand and the daughter strand
65
What does DNA polymerase III synthesise?
New strand directed by the template strand - DNA ligase seals the ends
66
What is Homologous recombination?
Repair of DNA double strand break
67
Where does the homologous recombination happen?
S and G2 phases - uses sister chromatid as a template - doesn’t create mutations
68
What is Non-homologous end joining?
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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