Cancer MOOC

Question 1

Discuss telomeres and cancer cells.

Answer 1

Normal cells - stop dividing when their telomeres become too short (hayflick’s limit)

	* telomere attrition, as a result of successive cell divisions, results in chromosomal instability
* Telomere - protein complex that protects end of chromosomes  (repetitive TTAGGG DNA sequence). They protect them from fusion and being recognised as sites of DNA damage.
* Telomeres are maintained by an enzyme called telomerase
* Normal cells: dysfunctional telomeres occur due to successive cell division which eventually shorten the length of the telomere - this then elicits DNA damage responses that trigger cellular senescence.
* Leads to breakage-fusion-bridge cycles where two sister chromatids without telomeres fuse together. (A dicentric chromosome - one with two centromeres) might be produced. Then during anaphase these are drawn apart and they break leading to genomic instability and extensive cell death.
* Some rare cells escape this and maintain stable but with short telomeres. They activate the normally silent human gene TERT that encodes telomerase - a reverse transcriptase enzyme
* Another DNA recombination mechanism (rarer) = Alternative Lengthening of Telomeres (ALT) also reverses telomere attrition
* hTERT activation - mutation in hTERT promoter (scientists have recently found 2 of these), alterations to alternative splicing of the hTERT pre-MRNA 
* Scientists have been investigating the molecular mechanisms which regulate hTERT expression and telomerase assembly
* telomerase inhibition strategies - hTERT inhibition - telomere shortens - cancer cell death
* Anti-telomerase therapeutics