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4/ CAN > Lecture 14 - Maintenance of Genomic Integrity > Flashcards

Lecture 14 - Maintenance of Genomic Integrity Flashcards

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1
Q

How what 3 ways can DNA damage occur?

A
  • copying error during DNA replication
  • spontaneous depurination
  • exposure to different agents e.g. background ionising radiation, UV light, tobacco products
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2
Q

What are the 5 major types of DNA repair?

A
  1. direct reversal of damage
  2. base excision - corrects DNA damage caused by reactive oxygen species deamination, hydroxylation, spontaneous depurination
  3. Nucleotide excision repair - removes adducts that produce large distortions in DNA
  4. Homologous recombination repair and non homologous end joining - repairs DNA double strand breaks
  5. DNA mismatch repair - repairs copy error made during replication
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3
Q

Name types of DNA damage

A
  • 7-methyl guanine
  • O6 alkyl guanine
  • UV induced thymine dimers
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4
Q

-

A
  • enzymatic reversal

- removal and replacement of damage

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5
Q

What are the three DNA damage substrates and their repair enzymes that can reversed?

A
  • UV dimers reversed by photolyase and visible light
  • O6 alkyl guanine reverse by alkyl transferase
  • DNA strand break reverse by ligases
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6
Q

What are the 3 substrates for base excision repair?

A
  • alkylated cytosine
  • spontaneous hydrolytic depurination of DNA
  • formation of DNA adducts after exposure to reactive small metabolites
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7
Q

Describe the process of base excision repair

A
  • the altered DNA base is excised in free form by a DNA glycosylase
  • the resulting abasic site is corrected by the concerted actin of:
  • an apurinic endonuclease
  • a DNA polymerase
  • a DNA ligase
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8
Q

What are the four steps of removal and replacement of a damaged base?
What enzymes are involved in each step?

A
  1. Removal = DNA glycosylase
  2. removal of apurinic site = apurinic endonuclease
  3. addition of new nucleotides = DNA polymerase
  4. ligation = DNA ligase
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9
Q

What dose nucleotide excision repair operate on?
What does it recognise?
What does it remove?

A
  • dsDNA, cannot act on ssDNA
  • it is non-specific, it recognises general distoriotns rather than specific adducts
  • will remove and repair large adducts e.g. thymine dimers
  • it is very efficient and error free
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10
Q

What are the four steps enzymes of nucleotide excision repair?

A
  1. endonuclease
  2. exonuclease - removes several or tens of nucleotides
  3. polymerase
  4. ligase
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11
Q

What is daughter strand gap repair?

A
  1. dimers remain after ‘repair’
  2. this is really a tolerance mechanism
  3. dimers are removed later from he double stranded DNA by excision repair
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12
Q

What is xerderma pigmentosum?

A
  • autosomal recessive disorder
  • patients show extreme sun sensitivity
  • patients develop many skin tumours
  • cultured skin fibroblasts show increases sensitivity to UV light
  • cells can be shown to have defect in DNA nucleotide excision repair
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13
Q

What is the defect in XP?

A
  • all deficient in NER, some have problem with daughter strand gap repair, many show unscheduled DNA synthesis
  • excision deficient XP patients there is failure to excise the damage
  • therefore the thymine dimer remains in situ
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14
Q

Describe the steps of nucleotide excision repair

A
  1. XPC (+XPE) recognise dimer
  2. XPB, XPD recruited to unwind DNA (helicases)
  3. XPF and XPG cleave
  4. polymerisation
  5. ligation
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15
Q

Mutation and Cancer in XP

A
  • XP cells show a high mutation rate
  • mutation probably due to unexcised dimers and, therefore, incorrect bases incorporated opposite damage
  • this mutation represents a step towards cancer development
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16
Q

Which gene is often mutated in XP?

A

PTCH1 (patch one)

17
Q

What are some of the variants of XP?

A
  • not deficient in nucleotide excision repair
  • not very sensitive to killing by UV, but cells are hypermutable
  • sensitive to UV can be enhanced by caffeine
  • defect in replication of DNA following UV exposure of cells (daughter strand gap repair)
  • deficient in an enzyme DNA polymerase h, which is able to replicate DNA past UV photoproducts - translation synthesis
18
Q

What main repair mechanism of BRCA1 and BRCA2 involved in?

A

double strand DNA break repair

19
Q

What are the differences in primary sequences of BRCA1 and BRCA2?

A 
BRCA1 = BRCT domains are found in many prairie proteins, as pairs of with an FHA domain 
BRCA2 = BRC repeats mediated binding to Rad51
20
Q

What findings suggested that BRCA1 and BRCA2 were involved in DNA DSB repair?

A
  • increased gamma ray sensitivity of BRCA1/2 -ve human cells and mice cells
  • increased sensitivity to gamma ray sensitive suggests a defect in DNA DSB repair
21
Q

By what two processes can DSB’s be repaired?

A
  • non-homologous end joining (NHEJ)

- homologous recombination repair (HRR)

22
Q

Describe homologous recombination repair and how BRCA2 and BCRA1 are involved

A
  • Rad51 coats ssDNA to form nucleoprotein filament that invades and pairs with homologous DNA duplex - initiating strand exchange
  • availability and activity of Rad51 is regulated by BRCA2
  • BRCA2 binds to Rad51 through the eight BRC repeats in BRCA2
  • BRCA2 controls intracellular movement and function of Rad51
  • release of Rad51 is triggered by DNA damage by phosphorylation of Rad51 or BRCA2
  • BRCA1 is also required for HRR
  • mechanism through interaction with and removal of 53BP1 at sides to DSB, prior to resection and recombination
23
Q

Describe the steps of non-homologous end joining

A
  • recognising of DNA ends
  • end synapsis
  • end processing
  • microhomology-based pairing
  • flap removal
  • gap filling and end ligation
24
Q

Describe the characteristics of NHEJ

A
  • Rad51 independent
  • BRCA2 not required for DNA DSB
  • V(D)J recombination is normal in BRCA deficient mice
  • NHEJ is an error prone process
25
Q

Give an overview of the roles of BCRA 1 and and BRCA2 in DNA damage responses

A
  • BRCA2 occurs quite specifically through control of Rad51 recombinase in homologous recombination
  • BRCA1 occurs in a much wider front, but links upstream sensing and signalling of damage, through 53BP1 in recombination repair
  • BRCA1 also has roles in cell cycle checkpoints
26
Q

How to PARP inhibitors work?

A
  • used to treated HRR deficient tumour cells
  • PARP1 usually acts to repair ssDNA breaks
  • this is inhibited by PARP inhibitors
  • when it reaches the replication fork, allows a dsDNA break forms
  • this cannot be repaired in these tumours, cell death
27
Q

What kind of an enzyme is Rad51

A

recombinase

28
Q

What does DNA mismatch repair do?

A

repairs copy errors made during DNA replication

  • mismatch repair genes reapir base-base mismatch
  • and repaired insertion deletion loops which arise as a consequence of polymerase slippage during replication. slippage cases gains or losses in repetitive DNA. also called micro satellite instability
  • genes that have microsattelites int heir coding region have an increase risk of mutation in HNPCC
29
Q

What mutation is found in hereditary non polyposis colorectal cancer?

A

mutation in mistmatch repair genes

30
Q

What is the mutator phenotype hypothesis in HNPCC?

A
  • microsattelite instability - led to mutator phenotype hypothesis
  • postulates that mismatch repair defects lead to mutation in other genes, including those known to play a role in the adenoma-carcinoma sequence
  • therefore, the increased mutation rate is then the cause of accelerated tumurigenesis
  • the mutator phenotype plays a role in tumour progression rather than in initiation

4/ CAN (39 decks)

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