HC4 - Maintenance of genomic integrity Flashcards
DNA stability
DNA is the most stable molecule in the cell
tissue organization
minimizes accumulation of mutations
small stem cell compartment
-stem cell DNA must be protected
- stem cells don’t divide often > reduces risk of errors
differentiated cells are prone to damage
- lung, colon, bile duct and epithelial cells > recycled quickly
- mutations are irrelevant
recycling colon cells
5-7 days
recycling keratinocytes
20 days
progression colonic crypt
stem cells > transit-amplifying cells > highly differentiated cells > cell death
maintenance of stem cell population through
symmetric and asymmetric division
stem cells are potential tragets of oncogenic transformation, because
they must be permantly present in tissue
dedifferentiation of transit-amplifying cells
killing of stem cells by cytotoxic carcinogens
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
protective mechanisms
- apoptosis
- drug pumps
- DNA replication
apoptosis intestinal stem cells
when a lesion occurs the intestinal stem cells will undergo apoptosis, instead of repairing the damage
cancer stem cells have
a reduced apoptosis potential and inreased repair
drug pumps
- stem cells pump out certain drugs more efficiently than differentiated cells
- high expression of multi-drug resistance 1 (MDR-1)
DNA replication as a barrier for mutagenesis
- low error rate polymerase
- proofreading
- 3’>5’ exonuclease activity
mismatch repair (MMR)
- can fix base mismatches during replication
- highly sensitive to altered DNA structure > bulges, loops
- must distinguish between parent and new strand
error rate replication
- replication = 1 in 10^5 nucleotides
- proofreading = 1 in 10^7
- MMR = 1 in 10^9
endogenous processes mutagenesis
-depurination, depyrimidination, deamination
- oxidation by ROS
- base mispairing
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
