Genome Instability Flashcards
What is genome instability
unscheduled alteration within genome
Genome instability in cancer
all malignant tumor show chromosomal abberations
patters varies aka alterations can be simple or complex
normally involve in initation of tumour but accumulate as tumor grows
type of genome instability
Chromosomal instability CIN - gains or losses of whole chromosomes as well as inversions,deletions,duplication and translocations of large chromosomal segments
nucleotide level instability - mutations of single or small groups of nucleotides
loss and gain of chromosomes
Chromosome spread
take mitotic chromosome and spread on slide and stain with dye
e.g. of loss and gain
trisomy 21 and pancreas cancer
translocations
can be seen through chromosome spread compared to chromosome paintaing where each is stained a different colour and can be balanced where ends are swapped or non balanced where one piece transfers
Deletions
deletions of large chunks shown due to staining and because banding patterns show due to dna being compact
duplications
same mthod of using banding patters of dna
after staing may shopw an extra band
inversions
same staining thing
where one region has been inverted in one chromosome
identifying nucleotide level changes
such as small insertions and deletions - PCR sequencing
single based changes sequence
outcomes of genome instability and cancer
point mutations - affect gene products - control
deletions of whole/partial chromosome - loss of gene product
duplication - possible interference in balance protein expression aka competing proteins affected
inversion/translocations - alterations of gene products/ gene control. generation fusion proteins with bad activity
is it always bad
can be neutral aka give silent mutaions (silent nucleotide polymorphisms)
can be positive - immune cells
processes causing instability
loss of high fidelity(aka safe guards_ during DNA replication in S-phase
errors during chromosome segregation
uncoordinated cell cycle progression
error prone repair of sproadic dna damage
What are the processes maintaining the high fidelity of dna repair
Polymerase accuracy
Mismatch repair
origin licensing
maturation of okasaki fragments
restart stalled replication forks
re-chromatinisation
preservation epigenetic signatures
Polymerase accuracy
Mismatch repair
what error is it ?
type of error
polymerase accuracy when polymerase puts in wrong base
point mutations
mismatch repair - cleans up after polymerase - point mutations
Origin licensing ?
what is it / type of error
happens once per S phase. Over replication gives amplication,DNA breackage and recombination. under gives potential loss of genome as well as above 2 .CIN
Origin licensing
over/ under
When this happens the extra strand is extruded, or reiniation with the other strand being forced in and then extruded
extruded strands can go into dna and cause homlogous recomb and cause dna breakage
in under
space between each replication bubble increases and thus certain areas wont be replicated and when split will create free ends
Maturation of Okasaki fragments error
retention RNA and generation of nicks and gaps
causing DNA breakage and recombination
CIN
Restart stalled replication forcks error
potential loss of genome on cell division and DNA breakage and recombination
RE-chromatinisation error
potential to stall replication leading to potential loss of genome on cell division,DNA breakage and recombination
Telomere maintenance error
Loss of sequences at chromosome ends,DNA breakage and recombination high susceptibility for translocations
Preservation epigenetic signatures error
lack of accurate transcriptional information
Errors during chromosome seqregation in mitosis
Chromosome condensation
sisterchromatid cohesion
kinetochore assembly and attachment
centrosome duplication and attachment
spindle formation
chromatid segregration
cytokinesis
all lead to CIN
Uncoordinated cell cycle progression
- G1/S checkpoint
– Insufficient energy levels
– Insufficient nucleotide levels
– Important protein complexes not in place so under replication - G2/M checkpoint
– Replication not finished
– Chromosomes not in right state for separation ( ie condensed) - Intra-S checkpoint
– Unresolved DNA damage present
– Stalled replication forks present - Spindle checkpoint
– Spindles not attached correctly to chromosomes - Post mitotic checkpoint
– Chromosome separation not complete.
Consequences of check point failure
point mutations may be fixed in new cells
cells may divide with incompletely replicated DNA
- chromsome may be pulled apart,this can lead to cells with broken chromosome ends and allow fusions
cells may divide carrying over re-replicated regions of DNA-Strand invasion, inappropriate fusions
cells may divide with chromosomes not properly attached to spindle- uneven distrabution of chromosomes
