Overview
Topic status: We're looking for students to study this topic.
The work proposed in this application focuses on the analysis of the DNA damage response pathway in human cells. This DNA damage response pathway is a crucial component of the surveillance network that maintains stability and integrity of our genome. Maintenance of genomic stability is critical for cellular homeostasis, with genomic instability leading to cancer or cell death. The ATM-dependent DNA Damage Response Pathway is specific for alteration in chromatin induced by one particular form of DNA lesion, DNA double-strand breaks (DSBs), that may be caused by normal genomic transactions such as meiotic recombination and the maturation of the immune system genes via V(D)J recombination, the cell's own metabolic environment (e.g hydrolysis and oxidation of DNA by endogenously generated reactive oxygen), error prone internal machinery (e.g. replication fork collapse), or may be due to exogenous agents such as ionizing radiation (IR), and certain chemotherapeutic drugs.
This exciting project will study the emerging field of synthetic lethality as a means to treating cancers. Specifically this project will initially utilise high content screens with a customs designed esiRNA library and then pursue candidates from this screen, determining their role in DSB repair and validating them as anti-cancer drug targets.
Hypothesis: Synthetic lethality was a term coined in yeast research. It describes a process where neither gene A or B are required for survival but loss of A and B is lethal.Currently there are four clinical trials being conducted using PARP inhibitors as synthetic lethal targets in BRCA null breast cancer patients. We hypothesise, that almost all cancers have defects in their DNA repair pathways, making synthetic lethality as very exciting therapy target strategy. Our study will identify new drug targets, new DNA repair proteins and will aim to classify breast cancers into sensitivity subclasses.
Aim 1: Screen PARP inhibited breast cancer cell lines with an esiRNA library to determine new components of the DSB repair pathway
Aim 2: Screen BRCA1&2 null cancer cells with esiRNA library to determine new synthetic lethality targets
Aim 3: Screen breast cancer cell lines to find commonality of sensitivities.
Aim 4: Validate and characterise most promising targets
Methods and techniques that will be developed in the course of this project:
- Cell culture, immunofloursecence microscopy, high content microscopy
- SDS PAGE, immunoblot, immunoprecipitation, transfections
- Study level
- PhD
- Supervisors
- QUT External Dr Derek Richard (QIMR)
- Organisational unit
Science and Engineering Faculty
- Research area
- Contact
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Please contact the supervisor.
Professor Judith Clements
