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Y2 MCD Cancer > carcinogenesis > Flashcards

carcinogenesis Flashcards

DNA damage and repair: explain how DNA can be damaged, recall the role of p53 in the detection of, and response to DNA damage, summarise the natural repair mechanisms for damaged DNA, explain how unrepaired DNA may become fixed as a mutation. Explain how the potential of a chemical / agent to damage DNA is assessed

1
Q

2 things which can damage DNA (possibly leading to mutations and cancer, but also by damaging DNA can be used in chemotherapy)

A

chemicals (carcinogens), radiation

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2
Q

6 sources of chemicals

A

diet, lifestlye, environment, occupation, medical, endogenous

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3
Q

3 sources of radiation

A

ionising, solar, cosmic

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4
Q

4 ways DNA is damaged by carcinogens (base pairs are planar, and have hydrogen bonds, so easily activated)

A

DNA adducts and alkylation, base dimers and chemical cross-links, base hydroxylations (e.g. by reactive oxygen species) forming abasic site (no base present in nucleotide), double and single strand breaks

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5
Q

what is phase I metabolism

A

addition of functional groups

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6
Q

3 reactions in phase I metabolism

A

oxidation, reduction, hydrolysis

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7
Q

what mainly mediates phase I metabolism

A

cytochrome P450

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8
Q

what is phase II metabolism

A

conjugation of phase I functional groups

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9
Q

6 reactions in phase II metabolism

A

sulphation, glucoronidation, acetylation, methylation, amino acid conjugation, glutathione conjugation

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10
Q

what does phase II metabolism generate

A

polar (water soluble) metabolites

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11
Q

what are polycyclic aromatic hydrocarbons (common carcinogens)

A

common environmental pollutants formed from combustion of fossil fuels or tobacco

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12
Q

structure of polycyclic aromatic hydrocarbons

A

polycyclic carbon rings, double bonds

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13
Q

example of a polycyclic aromatic hydrocarbon carcinogen

A

benzo[a]pyrene (B[a]P)

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14
Q

what is the 2 step epoxidation of B[a]P in liver

A

benzo[a]pyrene -(P450)-> benzo[a]pyrene-7,8-oxide -(EH)-> benzo[a]pyrene-7,8-dihydrodiol -(P450)-> benzo[a]pyrene-7,8dihydrodiol-9,10-oxide -> epoxide -> DNA adducts

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15
Q

result of DNA adduction by B[a]P

A

binds to bases in DNA, causing mutational changes

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16
Q

what is aflatoxin B1 formed by, and where is this common

A

A. flavus mould (common on poorly stored grains and peanuts)

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17
Q

what is aflatoxin B1

A

potent human liver carcinogen

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18
Q

epoxidation of aflatoxin B1

A

aflatoxin B1 -(P450)-> aflatoxin B1, 2,3-epoxide -> DNA binding on N7 position (adduction of guanine)

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19
Q

what cancer does aflatoxin B1 epoxidation cause

A

liver

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20
Q

what is 2-naphthylamine and what cancer does it cause

A

past component of dye-stuffs which is a potent human bladder carcinogen

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21
Q

metabolism of 2-naphthylamine

A

2-naphthylamine -(CYP1A2)-> N-hyroxy-2-naphthylamine -(glucuronyl transferase)-> glucuronide binds to NOH -(urine pH)-> breaks down to nitrenium ion -> DNA-reactive electrophile causing bladder tumours

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22
Q

other carcinogen from solar (UV) radiation and cancer caused

A

pyrimidine (thymine) dimers, causing skin cancer

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23
Q

other carcinogen from ionising radiation

A

IC free radicals

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24
Q

what do IC free radicals include

A

oxygen free radicals (super oxide radical O2. and hydroxyl radical HO.)

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25
Q

what do oxygen free radicals possess, and what do they therefore seek out

A

possess unpaired electrons, so are electrophilic and seek out electron-rich DNA

26
Q

what 3 things can happen during oxygen free radical attack on DNA

A

double and single strand breaks, apurinic and apyrimidinic sites (lose base), or base modifications

27
Q

3 stage process of base modifications during oxygen free radical attack on DNA

A

ring-opened guanine and adenine -> thymine and cytosine glycols -> 8-hydroxyadenine and 8-hydroxyguanine (mutagenic)

28
Q

what 2 factors influence rates of endogenous damage and repair

A

damage per hour, max repair rate (base pairs per hour)

29
Q

enzyme system most frequently involved in activation of chemicals to metabolites that can damage DNA

A

cytochrome P450

30
Q

what 3 things activate p53 during cellular stress (p53 lost in cancers as tumour suppressor gene)

A

mitotic apparatus dysfunction, DNA replication stress, double strand breaks

31
Q

what can p53 (transcription factor) activate

A

DNA repair

32
Q

4 types of DNA repair

A

direct reversal of DNA damage, base excision repair, nucleotide excision repair, during- or post-replication repair

33
Q

what happens during direct reversal of DNA damage: thymine dimers and methyl/alkylation

A

photolyase splits cyclobutane thymine dimers -> excise dimers; methyltransferases (e.g. MGMT) and alkyltransferases remove alkyl groups from bases

34
Q

what is base excision mainly for

A

apurinic/apyrimidinic damage (loss of bases), but no damage to phosphodiester bond and nucleotide (except base)

35
Q

what happens during base excision repair

A

DNA glycosylases remove base -> AP endonucleases remove remaining nucleotide -> repair polymerase (e.g. Polb) fills gap -> DNA ligase completes repair

36
Q

what is nucleotide excision repair mainly for

A

bulky DNA adducts

37
Q

what happens during nucleotide excision repair

A

endonuclease breaks two phosphodiester bonds either side of affected base (plus others) -> stretch of nucleotides either side of the damage excised by helicase -> repair polymerases (e.g. Pold/b) fill gap -> DNA ligase completes repair

38
Q

2 types of during- or post-replication repair

A

mismatch repair, recombinational repair

39
Q

base excision repair pathway

A

mutagen exposure -> DNA glycosylase removes mutagen and base attached to -> AP-endonuclease removes full nucleotide of removed base -> DNA polymerase adds correct base -> DNA ligase attaches correct nucleotide

40
Q

nucleotide excision repair pathway

A

mutagen exposure -> endonuclease breaks phosphodiester bonds either side of a stretch of nucleotides either side of damage -> helicase removes this stretch of nucleotides -> DNA polymerase adds correct bases -> DNA ligase attaches correct nucleotides

41
Q

persistence of damage and chance of mutagenic event relationship

A

greater persistence of damage, the greater the chance of mutagenic event relationship

42
Q

3 occasions when DNA double strand breaks are made

A

homologous recombination, physiological conditions during somatic recombination and transposition (variable region hypermutation in antibody), due to ionising radiation and oxidative stress

43
Q

role of KU proteins during DNA double strand break repair

A

KU proteins hold DNA, forcing double stranded DNA back from DNA fragments

44
Q

carcinogen-DNA damage 3 pathways

A

carcinogen damage leading to altered DNA -> [efficient repair and normal cell] OR [apoptosis and cell death] OR [incorrect repair/altered primary sequence -> DNA replication and cell division causes fixed mutations]

45
Q

outcome if fixed mutations effect transcription and translation

A

aberrant proteins

46
Q

outcome if fixed mutations are on critical targets

A

carcinogens

47
Q

2 examples of critical targets

A

oncogenes, tumour suppressor genes

48
Q

pathway of testing for DNA damage by potential carcinogen

A

structural alerts/SAR (predict if potential carcinogen) -> in vitro bacterial gene mutation assay -> in vitro mammalian cell assay -> in vivo mammalian assay -> investigative in vivo mammalian assays

49
Q

describe the bacterial (Ames) test for mutagenicity of chemicals e.g. bacteria which can’t make histadine on histadine-free media

A

chemical to be tested (potential carcinogen) and rat liver enzyme preparation (S9) -> bacteria that do not synthesise histidine e.g. Salmonella strain -> conversion of chemical to reactive metabolite -> able to make histadine so form colonies

50
Q

what is done to detect DNA damage in mammalian cells

A

treat mammalian cells with chemical in presence of liver S9 -> look for chromosomal damage

51
Q

what happens in in vitro micronucleus assays

A

cells treated with chemical and allowed to divide -> binucleate cells assessed for presence of micronuclei (show presence of DNA damage)

52
Q

in in vitro micronucleus assays, why might the kinetochore be stained

A

determine if chemical treatment caused clastgenicity (chromosomal breakage) or aneuploidy (chromosomal loss)

53
Q

what happens in bone marrow micronucleus assay in mice or rats

A

treat animals with chemical -> examine bone marrow cells or peripheral erythrocytes for micronuclei (test so if fed by carcinogen, do you see effect of carcinogen)

54
Q

normal spontaneous base modifications of DNA which must be corrected: deamination and examination

A

primary amino group unstable, so converted to ketogroups (e.g. cytosine to uracil)

55
Q

base modifications of DNA which must be corrected: chemical modification

A

normally oxidation reactions e.g. thymine oxidised to thymine glycol; by hyper-reactive oxygen species, radiation and chemical agents; bases alkylated or covalently linked to larger molecules (“adducts”)

56
Q

base modifications of DNA which must be corrected: photodamage

A

UV light absorbed by nucleic acid, inducing chemical change and forming thymine dimers (intra-DNA damage)

57
Q

4 types of DNA damage

A

single base pair mismatch (causes bulge), thymine diamer (distortion of helix), gap (removal of many nucleotides), nick (removal of single nucleotide by single break of phosphodiester bond)

58
Q

what is DNA mismatch repair

A

scrutinisation of DNA for bases that don’t pair properly, so proof-read by repliaction fork, with preference for newly synthesised strand

59
Q

when does DNA mismatch repair only occur

A

only during replication

60
Q

features of xeroderma pigmentosum caused by deficiencies of nucleotide excision repair

A

extreme sensitivity to UV light, causing severe pigmentation irregularities, melanomas and skin cancers, as well as other forms of cancer and neurological defects

61
Q

2 other diseases caused by deficiencies of nucleotide excision repair

A

trichothiodystrophy, Cockayne’s syndrome

62
Q

agents which overwhelm cells to cause DNA damage, so that they undergo apoptosis

A

alkylating, make bulky adducts, induce double strand breaks

Y2 MCD Cancer (20 decks)

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