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

HC4 - Maintenance of genomic integrity Flashcards by Dagmar Van Bergen

DNA stability

DNA is the most stable molecule in the cell

How well did you know this?

Not at all

Perfectly

tissue organization

minimizes accumulation of mutations

How well did you know this?

Not at all

Perfectly

small stem cell compartment

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

How well did you know this?

Not at all

Perfectly

differentiated cells are prone to damage

lung, colon, bile duct and epithelial cells > recycled quickly
mutations are irrelevant

How well did you know this?

Not at all

Perfectly

recycling colon cells

5-7 days

How well did you know this?

Not at all

Perfectly

recycling keratinocytes

20 days

How well did you know this?

Not at all

Perfectly

progression colonic crypt

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

How well did you know this?

Not at all

Perfectly

maintenance of stem cell population through

symmetric and asymmetric division

How well did you know this?

Not at all

Perfectly

stem cells are potential tragets of oncogenic transformation, because

they must be permantly present in tissue

How well did you know this?

Not at all

Perfectly

dedifferentiation of transit-amplifying cells

killing of stem cells by cytotoxic carcinogens

How well did you know this?

Not at all

Perfectly

Tomasetti & Vogel , 2015

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

How well did you know this?

Not at all

Perfectly

protective mechanisms

apoptosis
drug pumps
DNA replication

How well did you know this?

Not at all

Perfectly

apoptosis intestinal stem cells

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

How well did you know this?

Not at all

Perfectly

cancer stem cells have

a reduced apoptosis potential and inreased repair

How well did you know this?

Not at all

Perfectly

drug pumps

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

How well did you know this?

Not at all

Perfectly

DNA replication as a barrier for mutagenesis

low error rate polymerase
proofreading
3’>5’ exonuclease activity

How well did you know this?

Not at all

Perfectly

mismatch repair (MMR)

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

How well did you know this?

Not at all

Perfectly

error rate replication

replication = 1 in 10^5 nucleotides
- proofreading = 1 in 10^7
- MMR = 1 in 10^9

How well did you know this?

Not at all

Perfectly

endogenous processes mutagenesis

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

How well did you know this?

Not at all

Perfectly

depurination, depyrimidination and deanimation

due to hydrogen and hydroxyl ions

oxidation by Reactive Oxygen Species (ROS)

metabolic byproducts
creates SSBs, DSBs, abasic sites, protein crosslinks

exogenous agents mutagenisis (infrequent)

ionizing radiation
UV light
alkylating agents
cellular processes

ionizing radiation mechanism

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

UV light creates

ubiquititous
covalent bonds between adjacent pyrimidines

alkylating agents

- leads to loss of purine or pyrimidine bases - potent carcinogen > used in labs

cellular processes can

convert procarcinogens > formation of DNA adducts

example conversion procarcinogen

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

protection of DNA by cells

- physical shielding - ROS scavangers - Glutathoine S-transferases (GSTs)

physical shielding

melanocytes produce melanine

ROS scavanger

vitamin C, bilirubin, urate

Glutathione S-transferases (GSTs)

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

DNA repair mechanisms

- base-excision repair (BER) - nucleotide-excision repair (NER) - homologous recombination - non-homologous end joining

base-excision repair (BER)

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

nucleotide excision repair (NER)

- cuts out entire nucleotide - helix-distorting lesions > exogenous sources - transcription-coupled repair

defects BER/NER or MMR leads to

susceptebility cancer

xeroderma pigmentosum (XP)

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

DSB breaks

- can arise at stalled replication forks and induced by ionizing radiation - replication stress in cancer cells

DSB repair

- homologous recombination - non-homologous end joining

homologous recombination (HR)

active in S and G2 phase > sister chromatids needed

BRCA1/BRCA2 tumor suppressor genes

breast cancer

non-homologous end joining (NHEJ) = error prone

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

chromosomal aberrations

changes in structure > deletions, amplifications, translocations

chromothripsis

localized, massive chromosome fragmentations that lead to multiple rejoinings

polyploidy

multiplication of entire chromosome set > haploid, triploid, tetraploid

aneuploidy

changes in individual chromosome numbers

changes in chromosome numbers causes by

mitotic missegregation

nondisjunction

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

merotely

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

double-edged sword genetic instability cancer

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