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HMS Oncology > DNA Repair > Flashcards

DNA Repair Flashcards

1
Q

The substrate of PARP is. . .

A

NAD+

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2
Q

APEI endonuclease

A

Creates a 5’ single-stranded break at a site in the DNA double helix at an abasic site (presumably generated by DNA glycosylase).

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3
Q

DNA of all aerobically growing cells is exposed to reactive oxygen species during normal cellular metabolism

A
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4
Q

Mismatch repair mechanism

A
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5
Q

Role of p53 in the DNA Damage Response

A
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6
Q

Repair pathway overview

A
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7
Q

AP lyase

A

Creates a 3’ break on an already 5’ cleaved, abasic deoxyribose, freeing the deoxyribose and leaving a completely empty space on the DNA. Acts after APEI and DNA glycosylase in base excision repair.

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8
Q

Nonhomologous End Joining Mechanism

A
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9
Q

KU70/80

A

The first step of nonhomologous double strand break repair.

Recognizes breaks in the chromosome and brings in proximity, then recruits repair machinery.

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10
Q

DNA glycosylase

A

Flips a residue targeted for base excision repair out of the double helix and cleaves off its base, leaving the phosphodiesters and deoxyribose intact.

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11
Q

Nonhomologous End Joining

A

Predominant mechanism of double strand break repair. Utilized in the early cell cycle and G0, before DNA has replicated.

DSBs are recognized by a protein complex, broken strands of DNA are aligned, and then re-ligated. Process is error prone as it does not depend on homology. Also has potential to lead to a chromosomal translocation.

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12
Q

DNA Deminations

A

Deamination of cytosine and adenine represent a very common mechanism of DNA damage via hydrolysis reactions

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13
Q

Direct repair mechanism

A
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14
Q

Direct Repair

A

Simplest mechanism of DNA repair. An enzyme detects a base that has been damaged by addition of a functional group and removes the functional group. No further steps are taken.

Unfortunately, the utility of direct repair is limited to a small number of modifications.

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15
Q

Transcription-coupled repair

A

Occurs when RNA polymerase is transcribing DNA and runs into a “bump” in the DNA that prevents it from moving. This leads to recruitment of the nucleotide excision repair complex, which repairs the lesion and allows transcription once more.

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16
Q

Mismatch repair always assumes that. . .

A

. . . the daughter strand is the one with the mistake.

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17
Q

CHK1 and CHK2

A

Induced by ATM and ATR. Arrest the cell cycle in two ways:

  1. Phosphorylate p53, preventing Mdm2-mediated export into the cytoplasm and subsequent ubiquitin-proteasomal degradation.
  2. Activate Wee1 and inhibit Cdc25, preventing the transition from G2 to M.
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18
Q

Base Excision Repair and Single-Stranded Break Repair Mechanism

A
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19
Q

Nucleotide excision repair

A

Removes larger lesions which are capable of distorting the overall structure of the DNA. This may include large DNA adducts spanning multiple bases or base dimerization catalyzed by UV light.

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20
Q

Mismatch repair can detect _____.

A

Mismatch repair can detect all four types of possible mismatch.

21
Q

Master regulators of the DNA damage response

A

ATM and ATR

Both are protein kinases activated by MRN and KU (DNA breakage sensors), which in turn activate the distal transducers, CHK1 and CHK2, themselves kinases which induce p53-mediated cell cycle arrest.

22
Q

Mdm2

A

an E3 ubiquitin ligase for p53

23
Q

The cell’s system for recognizing kinks in DNA

A

23B and XP-C, then RPA

24
Q

Specificity in base excision repair relies on. . .

A

. . .the DNA glycosylases, which have evolved to recognize a number of different damaging DNA modifications.

25
Q

Apurinic/apyrimidinic (AP) sites

A

Most frequent type of DNA damage. Occur spontaneously by hydrolytic loss of purine or pyrimidine at a given locus.

26
Q

Poly-ADP ribose polymerase (PARP)

A

Recognizes a single stranded break in DNA (a missing residue on one side), and binds here. Generates Poly-ADP ribose at this site, a highly negatively charged polymer. This then recruits a repair complex, which removes the Poly-ADP ribose and attaches a DNA polymerase to fill in the single-nucleotide gap.

27
Q

Repair mechanisms for double-stranded breaks

A
  1. Homologous recombination is an error free mechanism, but this only works if there is a sister chromatid available to help repair the lesion (only in S or G2)
  2. Nonhomologous end joining operates in G1 or G0. This can repair the DNA, but does so with much higher error rates.
28
Q

Summary of Double-Stranded Break Repair Mechanisms

A
29
Q

Homologous Recombination diagram

A
30
Q

Pol β displays both ___ and ___.

A

Pol β displays both 5’→3’ polymerase activity and 3’→5’ exonuclease activity.

Thus it proofreads its last base added as it travels along the DNA polymerizing.

31
Q

Weinberg-emphasized DNA damage → p53 induction pathway

A
32
Q

XP-C and 23B

A

Recognize lesions that distort the shape of DNA. They then recruit TFIIH, a helicase that unwinds the DNA at this site. XP-G and RPA aid in the unwinding. Finally, XP-G and XP-F cut ~24-32 bases upstream and downstream of the lesion, creating a gap which will be filled in by Pol β.

33
Q

Base Excision Repair

A

Most common mechanism of DNA repair. Recognizes a wide variety of modifications.

Detects a single damaged base pair and removes one base, along with part of its phosphodiester backbone. Then, the excised base is repaired using a single base which is complimentary to the base left behind. This leaves a single-stranded break, which is then repaired by common single-strand break repair mechanisms.

34
Q

HMS-emphasized DNA damage → p53 induction pathway

A
35
Q

Mismatch repair

A

Corrects mistakes made during replication. It is key here that this machinery is designed to remove the mismatched base on the daughter strand, NOT the template.

36
Q

Homologous Recombination

A

Predominant mechanism of double strand break repair utilized in S phase and later in the cell cycle. This mechanism is nearly error-free.

DSBs are recognized by a protein complex which resects DNA away from the DSB to make single-stranded regions (sticky ends). Once these are generated, resected strands invade the sister chromatid strands by identifying regions of homology. The sister chromatids are used as a template for new synthesis.

37
Q

PARP mechanism

A
38
Q

Basic DNA Repair Model

A
39
Q

Nucleotide excision repair

A
40
Q

Basic steps of DNA repair

A
  1. Remove the damaged DNA
  2. Fill the gap
  3. Ligate the DNA
41
Q

Aflatoxin mechanism

A
42
Q

O6-MeG vs N7-MeG

A
43
Q

Futile cycles in nonfunctional DNA repair

A
44
Q

Lynch syndrome

A

caused by mutations in mismatch repair genes (MSH2, MSH6, MHL1), predisposes to development of colon cancer; 80% of patients carrying a mutation develop a tumor during their lifetime.

45
Q

Mutations in BRCA1 or BRCA2 genes

A

involved in homologous recombination, predispose to breast and ovarian cancer; 30-80% of patients with a mutation will develop breast or ovarian cancer, depending on which gene is mutated

46
Q

Mutations in XP

A

Xeroderma pigmentosum is due to mutation in nucleotide excision repair.

47
Q

Direct repair enzymes tend to. . .

A

. . .steal and sequester modifications. They are not a type of enzyme which may replenish itself and continue to catalyze the reaction, it is a one-to-one ratio. Once the resource has been exhausted, mutations in DNA will accumulate.

48
Q

Types of kinetochore attachment

A

HMS Oncology (11 decks)

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