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Cellulaire Oncologie > HC4 - Maintenance of genomic integrity > Flashcards

HC4 - Maintenance of genomic integrity Flashcards

1
Q

DNA stability

A

DNA is the most stable molecule in the cell

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2
Q

tissue organization

A

minimizes accumulation of mutations

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3
Q

small stem cell compartment

A

-stem cell DNA must be protected
- stem cells don’t divide often > reduces risk of errors

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4
Q

differentiated cells are prone to damage

A
  • lung, colon, bile duct and epithelial cells > recycled quickly
  • mutations are irrelevant
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5
Q

recycling colon cells

A

5-7 days

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6
Q

recycling keratinocytes

A

20 days

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7
Q

progression colonic crypt

A

stem cells > transit-amplifying cells > highly differentiated cells > cell death

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8
Q

maintenance of stem cell population through

A

symmetric and asymmetric division

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9
Q

stem cells are potential tragets of oncogenic transformation, because

A

they must be permantly present in tissue

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10
Q

dedifferentiation of transit-amplifying cells

A

killing of stem cells by cytotoxic carcinogens

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11
Q

Tomasetti & Vogel , 2015

A
  • the relationship between the number of stem cell divisions in the lifetime of a given tissue and lifetime risk of cancer in that tissue
  • 65% of differences in cancer explained
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12
Q

protective mechanisms

A
  • apoptosis
  • drug pumps
  • DNA replication
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13
Q

apoptosis intestinal stem cells

A

when a lesion occurs the intestinal stem cells will undergo apoptosis, instead of repairing the damage

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14
Q

cancer stem cells have

A

a reduced apoptosis potential and inreased repair

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15
Q

drug pumps

A
  • stem cells pump out certain drugs more efficiently than differentiated cells
  • high expression of multi-drug resistance 1 (MDR-1)
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16
Q

DNA replication as a barrier for mutagenesis

A
  • low error rate polymerase
  • proofreading
  • 3’>5’ exonuclease activity
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17
Q

mismatch repair (MMR)

A
  • can fix base mismatches during replication
  • highly sensitive to altered DNA structure > bulges, loops
  • must distinguish between parent and new strand
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18
Q

error rate replication

A
  • replication = 1 in 10^5 nucleotides
    • proofreading = 1 in 10^7
    • MMR = 1 in 10^9
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19
Q

endogenous processes mutagenesis

A

-depurination, depyrimidination, deamination
- oxidation by ROS
- base mispairing

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20
Q

depurination, depyrimidination and deanimation

A

due to hydrogen and hydroxyl ions

21
Q

oxidation by Reactive Oxygen Species (ROS)

A
  • metabolic byproducts
  • creates SSBs, DSBs, abasic sites, protein crosslinks
22
Q

exogenous agents mutagenisis (infrequent)

A
  • ionizing radiation
  • UV light
  • alkylating agents
  • cellular processes
23
Q

ionizing radiation mechanism

A
  • stips electrons from water > creates ROS
  • can also hit DNA directly
  • induces SSBs or DSBs
24
Q

UV light creates

A
  • ubiquititous
  • covalent bonds between adjacent pyrimidines
25
Q

alkylating agents

A
  • leads to loss of purine or pyrimidine bases
  • potent carcinogen > used in labs
26
Q

cellular processes can

A

convert procarcinogens
> formation of DNA adducts

27
Q

example conversion procarcinogen

A

alcohol > alcohol dehydrogenases (ADH) and aldehyde (ADLH) convert alcohol into mutagenic acetaldehyde

28
Q

protection of DNA by cells

A
  • physical shielding
  • ROS scavangers
  • Glutathoine S-transferases (GSTs)
29
Q

physical shielding

A

melanocytes produce melanine

30
Q

ROS scavanger

A

vitamin C, bilirubin, urate

31
Q

Glutathione S-transferases (GSTs)

A

inactivate electrophillic compounds (ROS) by linking them with glutathione > shut down in 90% of prostate adenocarcinomas

32
Q

DNA repair mechanisms

A
  • base-excision repair (BER)
  • nucleotide-excision repair (NER)
  • homologous recombination
  • non-homologous end joining
33
Q

base-excision repair (BER)

A
  • cleavage of the bond that links a modified base to a deoxyribose
  • non-helix distorting lesions > caused by endogenous sources
34
Q

nucleotide excision repair (NER)

A
  • cuts out entire nucleotide
  • helix-distorting lesions > exogenous sources
  • transcription-coupled repair
35
Q

defects BER/NER or MMR leads to

A

susceptebility cancer

36
Q

xeroderma pigmentosum (XP)

A

2000 times increase in risk of cancer, 8 genes, mostly NER

37
Q

DSB breaks

A
  • can arise at stalled replication forks and induced by ionizing radiation
  • replication stress in cancer cells
38
Q

DSB repair

A
  • homologous recombination
  • non-homologous end joining
39
Q

homologous recombination (HR)

A

active in S and G2 phase > sister chromatids needed

40
Q

BRCA1/BRCA2 tumor suppressor genes

A

breast cancer

41
Q

non-homologous end joining (NHEJ) = error prone

A
  • active in G1 phase
  • responsible for generating antibodies and T cell receptors
  • deficiency > severe immuno-deficiency
42
Q

chromosomal aberrations

A

changes in structure > deletions, amplifications, translocations

43
Q

chromothripsis

A

localized, massive chromosome fragmentations that lead to multiple rejoinings

44
Q

polyploidy

A

multiplication of entire chromosome set > haploid, triploid, tetraploid

45
Q

aneuploidy

A

changes in individual chromosome numbers

46
Q

changes in chromosome numbers causes by

A

mitotic missegregation

47
Q

nondisjunction

A

both sister chromatids are pulled to the same centrosome and end up in the same daughter cell

48
Q

merotely

A

a single chromotid is pulled by both centrosomes and leads to breakage

49
Q

double-edged sword genetic instability cancer

A
  • allows cancer to accumulate mutations for transformation
  • dysfunction of repair mechanisms leads to vulnerabilities for treatments

Cellulaire Oncologie (14 decks)

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