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BMS1. Replication and Repair (GELINAS) > DNA Repair (Gelinas) > Flashcards

DNA Repair (Gelinas) Flashcards

1
Q

Mutations are:

A
  1. stable changes in DNA sequence
    • substitutions, deletions, insertions
  2. can lead to phenotypic change in cell
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2
Q

Mutations can result from:

A
  • replication or recombination errors
  • damage by radiation (X-ray, ultraviolet, etc.)
  • damage by chemicals
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3
Q

Mutagens:

A

agents that damage DNA

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4
Q

Carcinogens:

A
  • mutagens that induce cells to become cancerous
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5
Q

The five types of mutations:

A
  1. replication errors
  2. damage to a single base
  3. bulky DNA adducts
  4. single-strand breaks
  5. double-strand breaks
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6
Q

Replication errors are corrected for by what pathway?

A

Mismatch repair (MMR)

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7
Q

Single base damage is corrected for by what pathway?

A

Base excision repair (BER)

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8
Q

Bulky DNA adducts are corrected for by what pathway?

A

Nucleotide excision repair (NER)

  1. Global genomic NER
  2. Transcription-coupled NER
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9
Q

Single strand breaks are corrected for by what pathway?

A

SSB repair

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10
Q

Double strand breaks are corrected for by what pathway?

A

DSB Repair

  1. non-homologous end-joining (NHEJ)
  2. homologous recombination
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11
Q

Repication error mutation characterisitics:

A
  • mismatched nucleotides
  • small insertion or deletion
  • no DNA damage
  • removed one-by-one
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12
Q

Single base damage mutation characteristics:

A
  • single DNA base modified
    • deamination, alkylation, oxidation, etc.
  • damaged base removed
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13
Q

Bulky DNA adduct mutation characteristics:

A
  • cause significant distortion in the helix
  • induced by radiation, chemicals, etc.
  • entire damaged oligomer is excised
  • repair pathway depends on whether adduct is in transcriptionally active or inactive region
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14
Q

Single strand break mutation characteristics:

A
  • induced by oxidative damage
  • break recognized
  • 3ʼ and/or 5ʼ end processing
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15
Q

Double strand break mutation characteristics:

A
  • Induced by ionizing radiation, oxidizing agents, topoisomerase inhibitors, etc.
  • two repair pathways
    • one error prone but quick
    • one non-error prone, but homology needed
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16
Q

In prokaryotes, strand-specificity for MMR is determined by:

A
  • DNA-methylation
    • how repair proteins determin which strand is new and which is the parent strand.
    • parent strand is methylated
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17
Q

In eukaryotes, strand-specificity for MMR is determined by:

A
  • presence of nicks between Okazaki fragments that have to be ligated
    • new strand has Okazaki fragments, parent strand does not
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18
Q

What proteins recognize mismatch mutations in human MMR?

A

MSH2/6

also recognize parent strand

19
Q

What proteins recognize insertions/deletions in human MMR?

A

MSH2/3

also recognize parent strand

20
Q

What endonuclease is involved in human MMR?

A

MLH1/PMS2

cleaves the newly synthesized strand on either side of the mismatch

21
Q

Steps in MMR pathway in humans:

A
  1. MSH2/6 recognize and bind to mismatches; MSH2/3 recognize and bind to insertions/deletions
  2. Endonuclease MSH1/PMS2 cleaves both sides of mismatched nucleotide
  3. Helicase and an exonuclease remove DNA
  4. DNA Pol III (deltaor epsilon wiht PCNA) inserts correct match
  5. DNA ligase seals
22
Q

Mutations in MSH2 or MLH1 of the human MMR pathway account for 90% of patients with:

A

Lynch Syndrome

23
Q

The Base Excision Repair pathway repairs:

A
  • spontaneously occurring DNA base modifications (e.g. base damage caused by deamination of cytosine into uracil, depurination, alkylation, oxidation etc).
24
Q

Steps in BER pathway in humans:

A
  1. base-specific DNA glycosylase recognizes damaged base
  2. same base-specific DNA glycosylase cuts the N-glycosidic bond between the damaged base and the sugar deoxyribose
  3. Helicase releases damaged base
  4. AP endonuclease cleaves sugar-phosphate backbone
  5. deoxyribose phosphate lyase activity removes the sugar-phosphate residue
  6. DNA Pol-beta fills the gap
  7. DNA ligase seals
25
Q

Damage recognition protein in BER pathway:

A

base-specific-DNA-glycosylase

26
Q

Damage recognition protein in MMR pathway:

A
  • MSH2/6 for mismatches
  • MSH2/3 for insertions and deletions
27
Q

Nucleotide Excision Repair (NER) is the only pathway that can remove:

A

bulky DNA adducts

28
Q

The two NER pathways:

A

1) Global genomic NER (GG-NER)
* INACTIVE DNA region
2) Transcription-coupled NER (TC-NER)
* ACTIVE DNA region

29
Q

GG-NER removes bulky DNA adducts in what types of DNA regions?

A

INACTIVE

30
Q

TC-NER removes bulky DNA adducts in what types of DNA regions?

A

ACTIVE

31
Q

Damage recognition proteins in GG-NER:

A
  • INACTIVE DNA region
  • XPA, XPC, XPE in humans
32
Q

Primary manifestation of bulky DNA adducts:

A
  • helix distortion
    • causes frameshifts
  • examples:
    • tobacco smoke chemicals binding to guanines
    • UV light causing T-T dimers
33
Q

Steps in GG-NER pathway:

A
  1. Repair proteins recognize helix distortion (XPC, XPE)
  2. Proteins nucleate assembly of repair complex (XPA)
  3. Excinucleases (endonucleases) make incisions 5’ and 3’ of lesion (XPF/ERCC1, XPG)
  4. helicase unwinds the DNA to release the damaged oligomer (XPB and XPD from TFIIH complex)
  5. DNA Pol-delta/epsilon with PCNA fills the gap
  6. DNA ligase seals the DNA
34
Q

TC-NER is triggered when:

A
  • helix distortion blocks progression of RNA polymerase II along the template strand
35
Q

TC-NER damage recognition proteins:

A

CSA and CSB

36
Q

What proteins recognize and ubiquitinate the stalled RNA Pol II in the TC-NER pathway?

A

CSA and CSB

37
Q

Steps in TC-NER repair pathway:

A
  1. helix distortion stalls RNA Pol II
  2. repair proteins recognize stalled RNA Pol II, ubiquinate it (CSA and CSB)
  3. RNA Pol II removed
  4. Other NER proteins recruited
  5. Helicase unwinds to create bubble
  6. damaged oligomer released
  7. Pol-delta/epsilon fills gap
  8. DNA ligase seals
  9. transcription resumes
38
Q

Single strand breaks are usually associated with:

A
  • loss of a single nucleotide
  • damaged 5ʼ- and/or 3ʼ-termini at the site of the break
39
Q

What repair protein recognizes single strand breaks in the SSB repair pathway?

A

PARP1

40
Q

Steps in SSB repair pathway:

A
  1. PARP1 recognizes single strand break
  2. XRCC1 is recruited, serves as molecular scaffold to recruit other repair proteins
  3. Many enzymes process broken ends
  4. Proper 3’-OH and 5’-phosphate groups restored
  5. DNA Pol-beta fills gap
  6. DNA ligase seals
41
Q

What is the major pathway for DSB repair?

A

Non-homologous end joining (NHEJ)

  • can occur anytime during cell cycle
  • error-prone, but better than a broken strand
42
Q

Steps in NHEJ DSB repair pathway:

A
  1. proteins recognize DSB, bind to broken ends
  2. above proteins facilitate strand alignment and recruitment of DNA-dependent protein kinase catalytic subunit (DNA-PKcs)
  3. WRN helicase opens strands
  4. Frayed ends removed by endonuclease
  5. DNA Pol fills gap
  6. DNA ligase seals
43
Q

Homologous Recombination Repair (HR) of DSB repair pathway:

A
  • requires alignment of homologous DNA molecules (sister chromatid present)
    • information from homologous sequence used to repair broken strand
  • NO ERRORS (non-mutagenic)
  • can only occur in S and G2 phases of cell cycle
44
Q

The human BRCA1 and BRCA2 proteins play major roles in:

A
  • the homologous recombination repair pathway in DSBs.
  • facilitates with RAD51 to search for homologous sequence on sister chromatid to align it with the broken strand

BMS1. Replication and Repair (GELINAS) (6 decks)

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