Biochemistry and cell biology of the cancer-associated enzyme telomerase

Summary

Telomerase is the enzyme responsible for lengthening the ends of chromosomes (telomeres), thereby allowing most cancer cells to divide indefinitely.  We are determining the mechanisms of telomerase function using biochemical and cell-based approaches, with the aim of developing telomerase inhibitors as cancer therapeutics.

Supervisor(s)

Associate Professor Tracy Bryan, Dr Scott Cohen

Research Location

Westmead - Childrens Medical Research Institute

Program Type

PHD

Synopsis

Our research is focused on understanding the role of the enzyme TELOMERASE in cancer. The ends of chromosomes are called telomeres, and consist of repetitive DNA sequences, together with many proteins. Research over the past two decades has shown that telomere shortening is the ‘molecular clock' that leads to senescence. Immortal cells all possess ways to overcome telomere shortening. This is most often achieved by the action of an enzyme called telomerase, a complex of protein and RNA that adds DNA sequences to the ends of chromosomes. Active telomerase has been detected in 85 - 90% of human tumours, and is not detected in most normal human cells.

Laboratory experiments have shown that blocking the action of telomerase causes tumour cells to die, at least in culture. This raises the exciting possibility that inhibitors of telomerase will be a very specific and non-toxic treatment for human cancer. Towards this aim, we are determining the mechanism of telomerase action, both biochemically and in cancer cells. We have made key discoveries regarding the composition of telomerase, how it gets recruited to telomeres, and how it interacts with its DNA substrate. The following project areas are some of the ways we are currently extending these discoveries:

1) Discovery of pathways of telomerase recruitment to telomeres, particularly the role of DNA damage response proteins in this process.
2) Elucidation of how telomerase extends four-stranded structures known as G-quadruplexes.
3) Determination of the mechanism of telomerase binding to its substrate and carrying out repetitive extension.

Additional Information

Children's Medical Research Institute (CMRI) is an award-winning state-of-the-art medical research facility, with over 100 full-time scientists dedicated to researching the genes and proteins important for health and human development. The CMRI is supported in part by its key fundraiser Jeans for Genes®. Our scientists are internationally recognised research leaders and foster excellence in postgraduate training. CMRI graduates are highly sought after nationally and internationally.

CMRI is located at Westmead, a major hub for research and medicine in NSW, and is affiliated with the University of Sydney. Easy to access by public transport.

We are looking for top quality students who can prove a dedicated interest and enthusiasm for scientific research.

Candidates may apply for a CMRI PhD Research Award, which exceeds the Australian Postgraduate Awards and NHMRC scholarships in value. Visit the CMRI website for more details

Methodologies:
Microscopy techniques including immunofluorescence, fluorescence in situ hybridisation (FISH), confocal microscopy, live cell imaging, automated image capture and quantitation.

Biochemical and molecular techniques including enzyme activity assays, DNA and RNA binding assays, molecular cloning, CRISPR-mediated gene editing, protein purification and chromatin immunoprecipitation.

Eligibility:
Honours entry: GPA on track for Hons I classification             
PhD entry: Hons I classification, lab-based research experience is preferable.


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Keywords

telomerase, telomeres, Cancer, Cell Immortalisation, chromosomes, DNA damage, enzymes

Opportunity ID

The opportunity ID for this research opportunity is: 111