Genome Instability

Question 1

What is genome instability

Answer 1

unscheduled alteration within genome

Question 2

Genome instability in cancer

Answer 2

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

Question 3

type of genome instability

Answer 3

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

Question 4

loss and gain of chromosomes

Answer 4

Chromosome spread
take mitotic chromosome and spread on slide and stain with dye

e.g. of loss and gain
trisomy 21 and pancreas cancer

Question 5

translocations

Answer 5

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

Question 6

Deletions

Answer 6

deletions of large chunks shown due to staining and because banding patterns show due to dna being compact

Question 7

duplications

Answer 7

same mthod of using banding patters of dna
after staing may shopw an extra band

Question 8

inversions

Answer 8

same staining thing
where one region has been inverted in one chromosome

Question 9

identifying nucleotide level changes

Answer 9

such as small insertions and deletions - PCR sequencing
single based changes sequence

Question 10

outcomes of genome instability and cancer

Answer 10

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

Question 11

is it always bad

Answer 11

can be neutral aka give silent mutaions (silent nucleotide polymorphisms)
can be positive - immune cells

Question 12

processes causing instability

Answer 12

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

Question 13

What are the processes maintaining the high fidelity of dna repair

Answer 13

Polymerase accuracy
Mismatch repair
origin licensing
maturation of okasaki fragments
restart stalled replication forks
re-chromatinisation
preservation epigenetic signatures

Question 14

Polymerase accuracy
Mismatch repair
what error is it ?
type of error

Answer 14

polymerase accuracy when polymerase puts in wrong base
point mutations

mismatch repair - cleans up after polymerase - point mutations

Question 15

Origin licensing ?
what is it / type of error

Answer 15

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

Question 16

Origin licensing
over/ under

Answer 16

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

Question 17

Maturation of Okasaki fragments error

Answer 17

retention RNA and generation of nicks and gaps
causing DNA breakage and recombination
CIN

Question 18

Restart stalled replication forcks error

Answer 18

potential loss of genome on cell division and DNA breakage and recombination

Question 19

RE-chromatinisation error

Answer 19

potential to stall replication leading to potential loss of genome on cell division,DNA breakage and recombination

Question 20

Telomere maintenance error

Answer 20

Loss of sequences at chromosome ends,DNA breakage and recombination high susceptibility for translocations

Question 21

Preservation epigenetic signatures error

Answer 21

lack of accurate transcriptional information

Question 22

Errors during chromosome seqregation in mitosis

Answer 22

Chromosome condensation
sisterchromatid cohesion
kinetochore assembly and attachment
centrosome duplication and attachment
spindle formation
chromatid segregration
cytokinesis
all lead to CIN

Question 23

Uncoordinated cell cycle progression

Answer 23

• 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.

Question 24

Consequences of check point failure

Answer 24

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