Telomere length elongation following treatment with chemotherapeutic drugs.
Aim: To investigate the mechanisms which leads to telomere length elongation after treatment with tricostatin A and azacytidine.
Telomeres are specialised structures, which are present at the ends of chromosomes and serve to protect the chromosome from degradation during cell division. Telomeres consist of a simple repeat sequence TTAGGG, which extends for up to 15kb in young normal human somatic cells, and are associated with a set of telomeric binding proteins collectively known as shelterin. During malignant transformation of normal cells, telomeres are maintained, although often still critically short, by the activation of the enzyme telomerase or rarely by the induction of the ALT (alternative lengthening of telomeres) recombinational telomere maintenance mechanism.
Our previous studies has shown that the chemotherapeutic drugs azacytidine and tricostatin A induce telomere length elongation in breast cancer cell lines [1, 2]. As mentioned above, telomere length increase is known to occur via two main processes, telomerase upregulation and/ or Alternative Lengthening of Telomeres (ALT). The objectives of this project will be to investigate which mechanism is responsible for the elongation observed after treatment and what affects this has on the biology of the cancer cells.
A range of molecular biology techniques will be used to carry out this investigation. This will include cell culturing, RNA, DNA, protein isolation, telomere length analysis using QFISH and qPCR, TRAP assay, C-Circle analysis. The MTT assay will be used to monitor drug sensitivity/resistance following exposure to azacytidine and tricostatin A.
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