Saurin Flashcards
Driving force of tumour evolution
Chromosomal instability
G1 checkpoints __________ conditions and G2 checkpoints __________ conditions.
G1 checkpoints external conditions and G2 checkpoints internal conditions.
External conditions
Cell-cell contact
Growth factors
Internal conditions
Cell size
Energy
DNA damage
____ levels remain high but _______ fluctuate depending on cell cycle stage.
CDK
Cyclins
CDK function
Phosphorylate proteins to progress cell cycle
Cyclin function
Bind to CDK to activate (releasing from inhibitor)
Substrate specificity
Which proteins induce cyclins?
Transcription factors
Ubiquitin ligases
How do cyclins overcome the threshold created by inhibitor proteins?
autophoshorylation and positive feedback
Cyclin D
Drives S phase entry with CKD4/6
Restriction point
Checkpoint
p53 activates p__ to cause inhibition and p__ to cause senesence.
21
16
Loss Of Heterozygocity
Losing a second allele when one is already mutated
LOH mechanisms
Gene loss
Chromosome loss (by aneuploidy)
Mutation duplication
How can a mutation be duplicated?
Template strand flips to other chromosome during replication
Mitotic recombination
Li-Fraumeni Syndrome
p53
Common tumour suppressor conditions
🦛☕️🍃
p53 drivers
hypoxia
ageing
ROS
DNA damage
infection
nutrient depletion
signals for hyperproliferation
Are p53 mutations recessive?
No, mostly missence
p53 structure
tetromer - 4 subunits each bind to DNA
___ is produced as biproduct of the cyclin pathway and activates p53.
ARF
How does p53 have 16 possible combinations?
Each subunit randomly gets a gene from one chromosome so a mutation on one chromosome can affect all subunits
How does p53 regress tumours?
Senscence
p53 and _______ operate within a negative feedback loop
MDM2
MDM2
E3 ubiquitin
ligase that promotes ubiquitylation and proteasomal degradation of p53
ARF binds to…
MDM2
p53 production
Constantly made and degraded
How does the APC gene organise the gut?
Cells proliferate at bottom of crypt, differentiate higher up
HIF1 drives transcription in hypoxia and is constantly degraded by…
VHL.
How does chromosomal instability drive tumour evolution?
Constant genome shuffling
Unattached kineticores in mitosis generate an inhibitor:
Mitotic checkpoint complex
What phosphorylates incorrectly attached kineticores?
Aurora B kinase
The mitotic spindle is __polar.
bi
What is cleaved in anaphase?
Cohesin complex
What does a multipolar mitotic spindle lead to?
Extra chromosomes pulled to one side
What does premature loss of cohesion mean?
Chromosomes cant match up
Describe proteotoxic stress
- chromosome imbalance
- proteomic imbalance
- constant degradation of
unstable proteins that are produced in excess
WGD
Whole genome doubling
How else does aneuploidy benefit tumours?
Inflammation
Mis-segregation can create weak micronuclei, leading to…
chromothripsis – massive rearrangement/shattering of chromosomes.
Pieces of DNA can attach to other chromosomes. What problems can this cause?
Can contain oncogenes
Can drive inflammation
Can activate immune response in cytoplasm
Can cause massive gene amplification on
extrachromosomal DNA (ecDNA)
What senses DNA in the cytoplasm
cGAS pathway
How do aneuploid cells cause inflammation?
Constant senescence
Immune response to DNA in the cytoplasm
FN and NFKb
How does inflammation promote tumours?
Extracellular matrix remodelling
Epithelial-Mesinchimal transition (EMT)
Invasion and metastases
Angiogenesis
Mutagens release (e.g. ROS)
Suppress apoptosis
Growth factors
Chromosomal instability can reduce expression of proteins
involved in…
antigen presentation.
Convergent evolution
Same selective pressure
Non-synonymous (dN): amino acid _________________
Synonymous (dS): amino acid _________________
Non-synonymous (dN): amino acid changes
Synonymous (dS): amino acid doesn’t change
Which genes drive cancer?
Genes with high rates of change are positively selected
Degenerate nucleotide code
Many codon sequences for 1 amino acid
Types of genetic diversity
Gene level changes
Chromosome level changes
Linear evolution
Stepwise evolution with driver mutation providing strong selective advantage so they outcome
neighbouring clones (selective sweeps)
List the different models of tumour evolution
Linear
Branched
Neutral
Punctuated
When does linear evolution occur?
Early tumourigenesis
Branched evolution
Clones diverge from common ancestor and evolve in parallel because they all
offer increased fitness
Give an example of branched evolution
Glioblastoma
Neutral evolution
Extreme case of branching evolution, in which all individuals in the population have equal fitness
When does neutral evolution occur?
Different stages of tumourigenesis (e.g. in between the gain of beneficial traits)
Punctuated evolution
Rapid burst of change followed by stable clonal expansions
Huge genetic diversity allows complex karyotypes to be selected
When does punctuated evolution occur?
copy number aberrations or chromosomal structural
rearrangements
Give examples of punctuated evolution
Chromothripsis
Genome doubling
What can be used to time “Most Recent Common Ancester” (MCRA)?
Clock mutations
Lethal cocktail
mutation + inflammation
dN/dS <1
deleterius
