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MCB 450 > Class 8: DNA damage, repair, and cancer > Flashcards

Class 8: DNA damage, repair, and cancer Flashcards

1
Q

10 hall marks of cancer

A
  • evading growth suppressors
  • avoiding immune destruction
  • enabling replicative immortality
  • tumor promoting inflammation
  • activating invasion and metastasis
  • inducing angiogenesis
  • genome instability and mutation
  • resisting cell death
  • deregulating. cellular energetics
  • sustaining proliferative signaling
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2
Q

endogenous damage types

A

replication errors –> mismatches
Spontaneous loss of nucleosides –> base altercation
chemical exposure –> base alteration

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3
Q

exogenous damage types

A

chemical exposure –> base alteration
UV Light exposure –> Thymine dimer
double strand break –> Ionizing radiation

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4
Q

it is estimated that each cell undergoes ____ DNA damaging events and. ____ replication errors per cell per day

A

> 20,000
10,000

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5
Q

Mutation types

A

chromosomal (segment) + point

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6
Q

chromosomal mutations

A

are mutations that involve changes to the entire chromosome or sections of it
- chronic myeloid leukemia

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7
Q

Point Mutations

A

are changes to one or a few base-pairs in the DNA in the for of substitution, deletion, or insertion

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8
Q

substitution point mutation

A

change of a nucleotide or a few from one type to another

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9
Q

insertion point mutation

A

an insertion of one or a few in the DNA sequence

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10
Q

deletion point mutation

A

a deletion of one or a few nucleotides in the DNA sequence

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11
Q

Substitution
pyrimidine –> pyrimidine
purine –> purine

A

transition

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12
Q

Substitution
purine –> pyrimidine
pyrimidine –> purine

A

transversion

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13
Q

Know the substitutions between AGCT

A
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14
Q

what could happen when there’s a disincorporated nucleotide in a mismatch

A

a) DNA polymerase delta moves backward and degrades recently synthesized strand, then polymerase moves forward again and undertakes once again to synthesize proper sequence

b) misincorporated nucleotide stays

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15
Q

oxidative deamination

A

GC to AT
-adenine deaminase

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16
Q

transition mutations

A

replace a purine with a purine or a pyrimidine with a pyrimidine

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17
Q

GC –> CG

A

transversion
-guanine deaminase

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18
Q

CG –>TA

A

transition
-cytosine deaminase
-most common point mutation in cancer cells

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19
Q

Oxidation: ROS such a hydroxyl radical

A
  • Guanine, the base component of dGMP in DNA, can be oxidized
    to 8-oxo-deoxyguanine.
  • 8-Oxo-deoxyguanine can base-pair with deoxyadenosine, rather than deoxycytidine

GC –> TA transversion

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20
Q

alkylation

A

the addition of a hydrocarbon molecule

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21
Q

methylation

A

most common type of alkylation
transfer of methyl group of CH3

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22
Q

depurination

A

cleavage of the glycosidic bond connecting purines to the backbone (2,000~10,000 purines/24 h/per cell)

  • destabilize the covalent bond to deoxyribose, resulting in the loss of the purine or pyrimidine base from DNA (AP sites, apurinic or apyrimidinic, abasic sites)
  • Triggered by endogenous metabolites undergoing chemical reactions
  • misread by the DNA polymerase
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23
Q

thymine dimer

A

Ultraviolet radiation (sunlight or tanning lamps) leads to cross-linking of adjacent pyrimidines (thymine) along one strand of DNA

UV

24
Q

double strand break

A

Ionizing radiations, including X-rays and radioactive decays, and free radical products of oxidative metabolism.

-radiation

25
Q

Cellular response to DNA Damage

A

Cell Cycle Check Point activation
Damage Tolerance
DNA Repair
Apoptosis

26
Q

checkpoint activation

A

pauses the cell cycle and gives the cell time to repair the damage before continuing to divide

27
Q

In G0 and early G1

A

Rb physically associates with E2F factors and
blocks their transactivation domain.

28
Q

In late G1

A

Rb-p releases E2F,
allowing the expression of genes that
encode products necessary
for S-phase progression.

29
Q

cyclin D1

A

the product of bel-1 gene`

30
Q

direct reversal repair

A

Cells are known to eliminate damage to their DNA by chemically reversing it.

These mechanisms do not require a template, since the types of damage they counteract can only occur in one of the four bases.

Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone.

31
Q

Methylation of guanine bases, is directly reversed by the protein …?

A

methyl guanine methyl transferase

32
Q

types of DNA repair

A

mismatch
base excision
nucleotide excision repair

33
Q

base excision repair (BER)

A
  1. Apurinic/apyrimidinic (AP) endonuclease is an enzyme that is involved in the DNA base excision repair pathway (BER).
  2. in the repair of damaged (deamination, alkylation) DNA. (8-oxo deoxyguanine, 3-methyladenine, deaminated bases)
  3. create a nick in the phosphodiester backbone of the AP site which is created when DNA glycosylase removes the damaged base.
34
Q

nucleotide excision repair

A
  1. Identification of the mismatched
    or mutated DNA strand
  2. Nick the mismatched DNA or mutated
    strand by endonuclease. Remove the
    mismatch or mutated DNA strand by
    exonuclease to create a gap.
  3. 5’-3’ DNA polymerase fill the gap
  4. DNA ligase forms the phosphodiester
    linkage
35
Q

nucleotide excision repair

A
  1. Identification of the mismatched
    or mutated DNA strand
  2. Nick the mismatched DNA or mutated
    strand by endonuclease. Remove the
    mismatch or mutated DNA strand by
    exonuclease to create a gap.
  3. 5’-3’ DNA polymerase fill the gap
  4. DNA ligase forms the phosphodiester
    linkage
36
Q

DNA Repair of UV-induced Thymine Dimer

A

-Exposure to ultraviolet light causes adjacent thymines
to become cross-linked, forming a thymine dimer and
disrupting their normal base pairing.

  1. Identification of the mismatched
    or mutated DNA strand
  2. An enzyme cut out and remove the damaged
    DNA. (Excision endonuclease, also called
    Excinuclease or UV-specific Endonuclease)
  3. 5’-3’ DNA polymerase fill the gap
  4. DNA ligase forms the phosphodiester
    linkage
37
Q

Double-Strand Break Repair

A

a) non-homologous end joining
b)homologous recombination repair

38
Q

LigIV

A

DNA Ligase IV, a specialized DNA ligase that forms a complex with the cofactor XRCC4, directly joins the two ends.

39
Q

slide 28

A

name - cancer - what kind of repair

40
Q

xeroderma

A

write facts

41
Q

carcinogens

A

agents that cause cancer directly

42
Q

procarcinogen

A

precursor of carcinogen. Turn into carcinogen in the body
-80% of cancer caused by environmental & food carcinogens

43
Q

salmonella his-strain

A

must be grown in the presence of Histidine, and the mutant allele is susceptible to back-mutation to a wild-type allele.

44
Q

ames test assys

A

many non-carcinogens are converted to carcinogens in the liver

small amount of rat liver is added to Ames test to mimic mammalian metabolism

45
Q

Conversion of procarcinogens to carcinogensby Cytochrome P450

A
46
Q

Intercalating Agents

A

Several hydrophobic molecules containing flat aromatic and fused
heterocyclic rings can insert between the stacked base pairs of DNA.

different from alkylating reagents

Ethidium bromide, Acridine orange, Actinomycin D

47
Q

oncogenes

A

cancer-causing genes
porto-oncogenes are the corresponding normal cellular genes that are responsible for normal cell growth and division
conversion of a proton oncogene to an oncogene can lead to abnormal stimulation of the cell type (gain of functions)

48
Q

proto oncogen abilities

A
49
Q

tumor suppressor genes

A

help prevent uncontrolled cell growth

mutations that decrease protein functions of tumor-suppressor genes may contribute to cancer onset (loss-of function, defect on two copies)

tuomr-suppresor routines : repair damaged DNA, control cell adhesion, inhibit the cell cycle in the cell-signaling pathway

50
Q

tumor suppressor genes pathways

A

inhibit cell division
promote apoptosis
inhibit immortality
inhibit angiogenesis
inhibit metastasis

all to inhibit malignant tumor progression

51
Q

multistep model for cancer development

A
  • Multiple mutations (5-7) are generally needed for full-fledged cancer; thus the incidence increases with age
  • At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes
52
Q

inference with normal cell signaling pathways

A

Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division,

Ras: oncogene, GTP-bound state of Ras
is the “on” state, and the GDP-bound state
is the “off” state.

mutations in the p53 gene prevent suppression of the cell cycle

53
Q

HNPCC
- name of gene
- cancer phenotype
- enzymes or process affected

A

4-5 genes
colonic polyposis
mismatch repair enzymes

54
Q

XP
- name of gene
- cancer phenotype
- enzymes or process affected

A

8 genes
UV-induced skin cancer
nucleotide-excision repair

55
Q

AT
- name of gene
- cancer phenotype
- enzymes or process affected

A

ATM
leukemia, lymphoma
response to dsDNA breaks

MCB 450 (11 decks)

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