L10 tumour biology

Question 1

how does rb control the g1 cell cycle checkpoint?

Answer 1

g0-g1 rb in dephos form recruits hdac to repress e2f-dp transcription factors. prevents transcription of cell progression genes- p300
early g1 cdk4/6-cyclin d complex can phosphorylate rb causing release of hdac and activation of e2f. tf of p300 which adds acetyl groups to histones for dna transcription. pass restriction point.
late g1- cdk2-cyce hyperphosphorylates rb= release= tf

Question 2

what is a telomere?

Answer 2

nucleoprotein

Question 3

what does stasis stand for?

Answer 3

stress or aberrant signalling induced senescence

Question 4

how can we prevent the dna damage response from recognising the ends of the chromsomes?

Answer 4

telomeres are bound by nucleosome arrays which prevent the access of telomerase.
suv39h1 methyltransferase trimethylates h3-k9. suv-20h can interact with rb proteins and allow trimethylation of h4-k20. together this prevents access to the chromatin from telomerase.

Question 5

what is alternative lengthening of telomeres?

Answer 5

uses homologous recombination
polymerase extends the telomere which allows maintenance of it within cancer
Short telomere invades a homologous strand and polymerase extends the telomere and this is the process of homologous recombination which allows maintenance of telomeric length.

Question 6

how can we turn on telomerase to initiate immortalisation?

Answer 6

mutations in tert promoter= de novo ets binidng site= tf can bind= telomerase made

mutations in e box around transcriptional start site= relief of maxmad1 complex= dysregulated gene expression

rearrangements or hepB insertions at enhancer regions near promoter= activation of gene

Question 7

what are some roles of telomerase in cancer that are not to do with telomere lengthening?

Answer 7

TERT associates with sp1 tf and facilitates cancer angiogenesis

TERT mediated aberrant dna methylation and silecing of tsgs

epithelial mesenchymal transformation via beta-catenin/ WNT pathway modulation

TERT interacts with NK-kB= incr expression of metalloproteases= invasion and metastasis

Question 8

name of the oligonucleotide telomerase inhibitor

Answer 8

imetelstat

Question 9

alternative telomerase inhibition cancer therapy

Answer 9

vaccine to hTERT peptides displayed throigh MHC 1= t cell response

adenovirus engineered to be controlled under TERT promoter. replication of lytic virus everytime telomerase is activated.