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DNA repair mechanisms Flashcards

1
Q

Can produce a covalent linkage between adjacent pyrimidine bases in DNA to form a thymine dimer

A

UV radiation

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2
Q

Repairs spontaneously-occurring DNA base modifications such as depurination and deamination, in addition to oxidation and alkylation base damage.

A

Base Excision Repair (BER)

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3
Q

Repairs bulky, helix distorting DNA lesions

A

Nucleotide Excision Repair (NER)

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4
Q

Repairs single-nucleotide mismatches and small insertion deletion mispairs

A

Mismatch repair (MMR)

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5
Q

The most frequent chemical reactions that can cause damage to DNA in cells are

A

Depurination and Deamination

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6
Q

Can release guanine as well as adenine from the DNA.

-This reaction occurs spontaneously when their N-glycosyl linkages to deoxyribose hydrolyze.

A

Depurination

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7
Q

How many purine bases are lost to depurination each day?

A

An estimated 5,000

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8
Q

Converts cytosine to uracil

A

Spontaneous deamination

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9
Q

In the care of depurination and deamination, the DNA backbone remains intact. The alterations in the bases are detected and repaired by the

A

Base excision repair pathway (BER)

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10
Q

In the BER, repair is initiated by enzymes, each of which recognizes a specific type of altered base in the DNA and catalyzes its hydrolytic removal. These enzymes are called

A

DNA glycolases

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11
Q

Once the damaged base is recognized, the DNA glycosylase reaction creates a deoxyribose sugar that

A

Lacks its base

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12
Q

This “missing tooth” is recognized by an enzyme that cuts the phosphodiester backbone and removes the damage. This enzyme is called

A

AP endonuclease

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13
Q

To replace the excised nucleotide, DNA polymerases execute repair synthesis. The final step of any DNA repair pathway is to seal the lingering DNA strand break or nick with

A

DNA ligase

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14
Q

Inherited mutations in the BER genes have not been

A

observed

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15
Q

Discontinuities in one strand of the DNA double helix and are usually accompanied by the loss of a single nucleotide and by a damaged 5’- and/or 3’-termini at the site of the break.

-considered to be a specialized sub-pathway of the BER

A

Single Strand Break Repair (SSBR) pathway

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16
Q

One of the most common source of SSBs is

A

Oxidative attack by Rective Oxygen Species (ROS)

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17
Q

Which is more common (by three orders of magnitude) SSBs or DSBs?

A

SSBs

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18
Q

Disintegration of oxidized deoxyribose is primarily detected by?

-Rapidly binds to, and is activated by, DNA strand breaks

A

PARP1

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19
Q

Serves as a molecular scaffold for multiple repair proteins, and stimulates multiple enzyme components of SSB repair

-accelerates the overall SSBR process

A

X-ray repair cross-complementing protein 1 (XRCC1)

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20
Q

Consequences of unrepaired SSBs include the following:

A

Collapse of dNA replication fork during S phase (forming DSBs); stalled transcription; increased cell death through PARP1 activation

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21
Q

Which polymerase fills the SSB?

A

Polymerase β

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22
Q

A rare autosomal recessive spinocerebellar ataxia syndrome that resembles ataxia telangiectasia, but lacks the non-neurologic features such as immune deficiency and telangiectasias.

A

Ataxia Oculomotor Apraxia (AOA1)

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23
Q

The characteristic features of AOA1 seem to be variable onset (1-16 years)

A

Cerebellar atrophy, ataxia, late axonal peripheral neuropathy, and oculomotor apraxia

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24
Q

The shaky and unsteady movements that result from the brains failure to regulate the body’s posture and the strength of direction movements

A

Ataxia

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25
Q

Ataxia is most often caused by disease activity in the

A

Cerebellum

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26
Q

A neurological condition characterized by loss of the ability to perform activities that a person is physically able and willing to do

A

Apraxia

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27
Q

Limited eye movement on command

A

Oculomotor apraxia

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28
Q

Has other features include cognitive impairment, hypercholesterolemia, hypoalbuminemia, and involuntary movements.

A

Ataxia Oculomotor Apraxia (AOA1)

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29
Q

The gene mutated in AOA1 was identified and designated as

A

Aprataxin (APTX)

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30
Q

Has putative repair mechanism for 5’ breaks (a DNA “End Processor”).

A

Aprataxin (APTX)

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31
Q

Unlike ataxia telangiectasia, AOA1 cells are only mildly sensitive – if at all- to

A

Ionizing radiation

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32
Q

There is no increase in cancer seen with this syndrome, nor increased chromosomal instability following ionizing radiation.

A

AOA1

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33
Q

Might be more dependent on APTX for DNA end processing than other post-mitotic cells, owing to a more limited availability of alternative end-processing factors.

-One reason why AOA1 might target nervous system

A

Neurons

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34
Q

AOA1 may also be largely restricted to the nervous system because of the

A

High levels of oxidative stress encountered by the nervous system

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35
Q

The limited regenerative capacity of neurons, compared with other non-cycling cell types that are more readily replaced by precursors, might render this tissue particularly sensitive to

A

Cell dysfunction or loss

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36
Q

Consists of a series of reactions that can repair damage caused by any large change in the structure of the DNA double helix.

A

NER pathway

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37
Q

In this pathway, a multienzyme complex scans the DNA for a distortion rather than for a specific base change or nick

A

Nucleotide Excision Repair (NER)

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38
Q

In the NER, once the bulky lesion has been found, the phosphodiester backbone of the abnormal strand is cleaved on both sides of the distortion, and an oligonucleotide containing the lesion is removed from the helix by a

A

DNA helicase

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39
Q

Broadly speaking, mutations that affect the repair process of non-transcriptionally active regions (the global genomic nucleotide excision repair pathway, GG-NER) are associated with

A

Skin Cancer

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40
Q

Mutations that affect the transcription-coupled nucleotide excision repair (TC-NER) pathway contribute to more

A

Developmental and Neurological disorders

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41
Q

The major damage recognition proteins for the GG-NER pathway

A

Xeroderma pigmentosum protein (XPC) or XPE

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42
Q

Mutations in XPC or XPE lead to

A

Non-neurological Xeroderma Pigmentosum

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43
Q

Non-neurological Xeroderma Pigmentosum is typified by

-these patients DO NOT have neurodegenerative symptoms

A

Extreme solar sensitivity and increased risk of skin cancer (2000x)

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44
Q

XPC and XPE detect

A

Helical distortions within the DNA

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45
Q

Mutations in XPC result in reduced capacity for the repair of lesions such as

A

Cyclobutane pyrimidine dimers

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46
Q

Most mutations in XP-C are inactivating null mutations, indicating that XP-C disease is largely due to a

A

Loss of enzyme function

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47
Q

Even low levels of XP-C protein produced by splice site mutations are enough to reduce UV sensitivity and create a milder phenotype. This suggests that levels of GG-NER gene products in normal cells are in

A

Excess of what is actually needed

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48
Q

A rare autosomal recessive genetic disorder characterized by numerous skin abnormalities ranging from excessive freckling to multiple skin cancers.

-The first DNA-repair disorder to be identified

A

Xeroderma Pigmentosum (XP)

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49
Q

Patients with XP with mutations in the GG-NER pathway develop symptoms at a median age of 1 to 2 years, although onset after 14 years old occurs in

A

5% of patients

50
Q

Sixty to ninety percent of patients with XP develop

A

Ocular abnormalities

51
Q

Do individuals that are heterozygous for XP have symptoms?

A

No

52
Q

Patients with XP also have a 10- to 20-fold increase in the incidence of internal neoplasms such as

A

Brain, lung, and gastric tumors

53
Q

Patients with mutations within the common pathway of NER such as XP-D and XP-A display both

A

Exterme sun sensitivity AND neurodegeneration

54
Q

Caused by mutations in CSA or CSB, proteins that recognize DNA damage in transcriptionally active regions.

A

Cockayne Syndrome (CS)

55
Q

The helix distortion caused by the DNA damage blocks RNA polymerase II progression, and the stalled RNA polymerase helps to initiate the

A

TC-NER repair process

56
Q

The diagnosis of Cockayne Syndrome (CS) depends on the presence of what three signs?

A
  1. ) Growth retardation
  2. ) Abnormal sensitivity to light (photosensitivity)
  3. ) Prematurely aged appearance (progeria)
57
Q

Patients with CS show severe developmental and neurological symptoms, but despite their photosensitivity, they do NOT manifest

A

Cancer

58
Q

CS patients are often normal at birth but experience failure of brain growth and progressive neurologic dysfunction manifested by developmental delay, as well as behavioral and intellectual deterioration due to

A

Demylination of Neurons

59
Q

One explanation for the differences in CS when compared with XP is that transcription does not recover after RNA polymerase is blocked. Furthermore, the arrested RNA polymerase is a potent inducer of

A

Apoptosis

60
Q

A DNA repair pathway that is conserved from bacteria to humans

-Gretly improves the fidelity of replication (50-1000 fold)

A

MMR

61
Q

A Hallmark of many MMR-deficient cells is instability at

A

Microsatellite regions (Microsatellite instability [MSI])

62
Q

Repetitive DNA sequences of 1-4 base nucleotides that are particularly susceptible to DNA replication erros when the MMR system is absent

A

Microsatellites

63
Q

In cancer cells, the presence of a defective MMR system leads to the accumulation of unrepaired mitotic errors, which occur more frequently in repetitive DNA tracts, mainly owing to the

A
  1. ) Slippage of error prone DNA polymerase

2. ) The occurrence of DNA helix hairpins at the replication fork

64
Q

Widely used as a diagnostic marker for loss of MMR activity in tumor cells

A

MSI

65
Q

The polymerase chain reaction (PCR)-based analysis of microsatellite regions is based on the comparison of their presence and length among patients or between

A

Normal and malignant cells

66
Q

A microsatellite is considered unstable if the distribution of the fragments from the tumor sample differs from that of the

A

Normal tissue

67
Q

Only 3-4% of colon cancers are

A

Hereditary

68
Q

The most common inherited colon cancer characterized by an increased risk of colorectal cancer and other cancers. It is a common autosomal dominant syndrome characterized by early onset (average age

A

Lynch Syndrome (aka hereditary nonpolyposis colorectal cancer HNPCC)

69
Q

The occurrence of neoplastic legions in tissues including endometrial, skin, ovarian, gastric, and renal, are an indicator of

A

Lynch Syndrome

70
Q

The diagnosis of Lynch syndrome can be determined using the Amsterdam Criteria I, II and then by molecular genetic testing for germline mutations in

A

Mismatch repair genes

71
Q

A hallmark of Lynch syndrome is

A

MSI

72
Q

A particularly severe threat to genome stability that, if left unrepaired, could cause loss of chromosome fragments during mitosi, or chromosomal translocations that induce neoplastic transformation

A

Double-stranded breaks (DSBs)

73
Q

To prevent loss of genetic material during mitosis cells

A

Arrest cell cycle at G2/M boundary until DSBs are repaired

74
Q

If a tumor suppressor gene loses heterozygosity, the cell can eliminate the dangers of the DSBs by inducing

A

Apoptosis

75
Q

Common DNA lesions induced by many types of stress and exposure, including ionizing radiation, oxidizing agents, replication errors and certain metabolic products.

A

DSBs

76
Q

Which types of drugs can induce DSBs?

A

Certain antineoplastic drugs such as bleomycin, anthracyclines, and topoisomerase inhibitors

77
Q

DSBs can be visualized by immunochemical staining for foci enriched in

A

Phosphorylated histone H2AX

78
Q

DSBs can be repaired by which two fundementally different mechanisms?

A
  1. ) Non-homologous end joining

2. ) Homologous recombination

79
Q

In mammalian cells, this repair pathway is probably restricted to the S and G2 phases of the cell cycle when a sister chromatid is present

A

Homologous recombination

80
Q

Involves rejoining what remains of the two DNA ends, and the mechanism has evolved in a manner that tolerates nucleotide loss or addition at the rejoining site

A

Non homologous end joining (NJEJ)

81
Q

An autosomal recessive, complex, multisystem disorder characterized by progressive neurologic impairment, cerebellar ataxia, variable immunodeficiency with susceptibility to sinus and lung infections, impaired organ maturation, x-ray hypersensitivity, ocular and cutaneous telangiectasia, and a predisposition to malignancy

A

Ataxia Telangiectasia (AT)

82
Q

Small dilated blood vessels near the surface of the skin or mucous membranes. They can develop anywhere on the body but are commonly seen on the face around the nose, cheeks, and chin

A

Telangiectasias

83
Q

The protein mutated in AT, that is normally activated by DNA DSBs and signals to the cell cycle checkpoint to slow the passage of cells through the cell cycle to facilitate DSB repair.

A

ATM

84
Q

It seems likely that ATM also signals to the DNA repair machinery to facilitate

A

DNA repair

85
Q

Subsequent studies suggest that, in the absence of ATM, persistent DNA DSBs are localized to

A

Heterochromatin

86
Q

Seems to facilitate the entry of the DNA repair machinery into heterochromatin

-also responds to physiologic breaks in DNA during the development and differentiation of B and T cells

A

ATM

87
Q

Up to 30% of AT patients develop

A

Lymphoid tumors

88
Q

One of the most highly conserved groups of DNA helicases

-contribute to the maintenance of genome stability across various species

A

RecQ helicases

89
Q

Defects in at least three of five human RecQ homologues are responsible for defined genetic diseases, and we refer to these as

A

Bloom’s syndrome (BS), Werner’s syndrome (WS), and RECQ4 syndromes

90
Q

What are the RECQ4 syndromes?

A

Rothmund-Thompson syndrome (RTS), Rapadilino, and Baller-Gerol syndrome (BGS)

91
Q

Interact with several proteins that have essential roles in DNA repair and may interact with specific DNA repair pathways

A

RecQ proteins

92
Q

Has been implicated in BER of ROS induced damage, methylation-induced DNA damages and SSBs

A

WRN (A ReQ Helicase) (mutation of which causes Werner Syndrome)

93
Q

Most of the mutations in WRN, a protein with ATPase, helicase, exonuclease, and single-strand annealing activities, lead to truncations of the protein, and/or elimination of a crucial nuclear localization signal that prevents WRN from finding its way to the

A

Nucleus

94
Q

WRN has been shown to physically and functionally interact with key proteins involved in NHEJ and HR, which suggests an important role of WRN in

A

DSBR

95
Q

A rare autosomal recessive disorder caused by mutations in the WRN gene

-Generally patients exhibit a stocky appearance

A

Werner’s syndrome

96
Q

Generally, the first clinical sign of WS is a lack of

A

Pubertal growth during teen years

97
Q

In one study, 95% of WS patients were reported to have

A

Short stature

98
Q

In their 20’s and 30’s, patients with WS begin to manifest

A

Skin atrophy, loss of hair, and graying hair

99
Q

Have telomere shortening, chromosomal rearrangements, increased susceptibility to malignant transformations and frequent telomere fusions.

A

WS cells

100
Q

Mutations in which three genes give rise to the combined symptoms of the NER diseases XP and CS?

A

XPA, XPB, XPD, XPG, and XPF

101
Q

The nervous system is very sensitive to

A

DNA damage

102
Q

The neurological symptoms are almost the exclusive presentation of the disease in

A

DNA SSBR deficiencies

103
Q

What may account for the sensitivity of the nervous system to DNA damage?

A

Brain metabolizes 20% of oxygen, but has a lower amount of antioxidants than any other part of the body

104
Q

Neurons are particularly susceptible to

A

Reactive oxygen species (oxidative stress)

105
Q

Active transcription can be estimated to involve only about 1–2% of total genomic DNA indicating that the lethal (apoptotic) signal generated by a failure of TCR of active genes must be about 50 to 100 times as potent per unit of repairable DNA, as is the signal for lethal events from a failure

A

GG NER

106
Q

Might be a source for the pathological consequences in CS and cause cell loss from non-dividing tissues such as brain and retina

A

The potent apoptotic signal generated by failure of TC-NER

107
Q

Apoptosis that removed damaged cells from the skin would conversely prevent UV-light carcinogenesis, especially in

A

CS cells

108
Q

Oxidative damage has been reported in the brains of repair-deficient patients. Some tissues that degenerate in CS appear to be unusually sensitive to oxygen levels, including the

A

Purkinje and Retinal cells

109
Q

The initial damage response in TC NER is mediated by the coupling factors

A

CSA and CSB

110
Q

Has a repair mechanism for 5’ breaks

-mutation of this gene results in AOA1

A

Aprataxin (APTX)

111
Q

Major damage recognition proteins for the GG-NER

A

XPC and XPE

112
Q

WRN has been implicated in

A

Base excision repair of ROS oxidative damage, methylation induced DNA damage, SSBs, and DSBs

113
Q

Ataxia Oculomotor Apraxia is due to a molecular defect in

A

Aprataxin (APTX)

114
Q

What DNA repair pathway is affected by AOA1?

A

Single-stranded break repair pathway

115
Q

Ataxia telangiectasia is due to a molecular defect in

A

AMT

116
Q

What DNA repair pathway is affected by AT?

A

Double-stranded break repair

117
Q

Cockayne syndrome is due to a molecular defect in

A

CSA or CSB

118
Q

What do CSA and CSB do?

A

Recognize the stalled polymerase, remove it, and recruit other proteins to fix damage

119
Q

What DNA repair pathways are affected by mutation in the ReQ Helicase WRN?

A

BER, SSBR, DSBR

120
Q

Mutations in XPA and XPD are mutations that affect the common pathway. This disease is still referred to as

A

XP

BMS (62 decks)

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