Telomere deprotection and cancer

Summary

Genome stability in human cells is maintained through the coordinated functions of the DNA damage response. We study these processes with particular interest in the pathways that respond to telomere deprotection in ageing and cancer cells.

Supervisor(s)

Dr Tony Cesare

Research Location

Westmead - Childrens Medical Research Institute

Program Type

PHD

Synopsis

Telomeres are the protective nucleoprotein structures at chromosome ends. They function to protect chromosome termini, and prevent activation of the DNA damage response and illicit DNA repair activity at the naturally occurring chromosome ends. As a consequence of normal ageing, telomeres shorten each time a cell divides. In human cells, progressive telomere shortening is a potent tumour suppressor mechanism that prevents unlimited cell growth in the presence of cancerous mutations.
Our laboratory has identified that telomeres exist in three different structural states. "Closed-state" telomeres prevent activation of the telomere DDR, while "Uncapped-state" telomeres are subjected to DNA repair activity that covalently links chromosome ends together. In between these fully protected and completely unprotected states, lies an "Intermediate-state", which is the critical feature governing Telomere-dependent tumour suppression. Intermediate-state telomeres are unique in that they can activate the DNA damage response and arrest cell growth, while simultaneously inhibiting DNA repair. This enables aged cells to activate a warning signal, and stop proliferation, while simultaneously preventing further genomic instability that can lead to cancer. We were also part of the team that identified telomeres transition from the closed- to intermediate-state during prolonged mitosis, and that this serves as a signalling mechanism to kill human cells with genome instability. This discovery exposed a complex, but poorly understood, relationship between telomeres and cell division, which we continue to actively explore.
Much of our research now focuses on understanding how telomeres govern cell cycle arrest, and the relationship between telomere protection and mitosis. We have opportunities in our laboratory to study telomere biology in relation to genome stability, tumour suppression, cell signalling and mitosis, using cutting edge techniques. Projects will be tailored to applicants interests and strengths on an individual basis.

Additional Information

Methodologies:Cell and Molecular Biology; Viral vector based gene expression modification (shRNA, CRISPR); Live cell imaging (widefield and confocal); Fixed imaging (confocal and widefield); Automated image capture and analysis; Super-resolution microscopy; Cell based assays to measure genome instability and viability; Flow cytometryStandard molecular biology and biochemistry (western blot, Chromatin Immunoprecipitation, etc); Mass-spectrometry (for selected students with interest and previous experience). 
Eligibility:
Honours entry: GPA on track for Hons I  classification.    
PhD entry: Hons I classification, lab-based research experience is preferable. Our lab has a strict policy that all Ph.D. candidates must attract external funding (such as an APA, IPA, IPRS, etc). 

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Keywords

tumour suppression, genome stability, DNA damage response, mitosis, microscopy, molecular biology, confocal microscopy, telomeres, Cancer, Cell biology, live cell imaging, super resolution microscopy

Opportunity ID

The opportunity ID for this research opportunity is: 2072

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