Regulation Of The Quality Of DNA Repair By Timing In The Cell Cycle
Funder
National Health and Medical Research Council
Funding Amount
$468,794.00
Summary
During responses to infection or immunisation, antibody-producing _B� cells mutate their antibody genes at extreme rates. Rare mutations which improve the antibodies are selected by competition between B cells favouring those which make the best antibodies: Darwinian evolution on extreme _fast-forward�. We aim to understand this process because it is essential for normal immunity and effective vaccination, and because when it goes wrong, it can cause aggressive human cancers.
A Tumour Suppressor Pathway That Removes DNA-RNA Hybrids
Funder
National Health and Medical Research Council
Funding Amount
$935,780.00
Summary
DNA:RNA hybrids are found normally in our chromosomes. But, the regions where DNA:RNA hybrids form are linked to chromosome changes that occur during breast and blood cancer development. We have uncovered why these chromosome changes occur, and have linked it to the important function of a cancer-associated gene called FANCM. Our study is exploring this important finding that has implications for both the cause and treatment of cancer.
Biochemical Reconstitution Of The Ubiquitin Ligase Pathway Defective In Fanconi Anaemia
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Fanconi Anemia (FA) is characterised by loss of vital blood cells but also 700x risk of developing leukaemia and other cancers. FA is caused by an inherited defect in one of 15 different genes that provide a signal and repair mechanism protecting cells from cancer causing mutations. By reconstructing this signaling mechanism in the test tube we will determine how it contributes to cancer protection, and highlight potential strategies for treatment of FA and leukaemia in the general population.
Multi-domain Regulation Of DNA Damage Response Kinases
Funder
National Health and Medical Research Council
Funding Amount
$313,427.00
Summary
DNA damage plays a key role in the onset of cancer and the response to cancer therapies. Mutations in the Chk2 DNA damage response kinase are associated with increased cancer risk. We will study detailed mechanisms how phosphorylation of Chk2-like kinases contributes to normal copying of our DNA every time a cell divides, and how it regulates how Chk2 is activated. The studies will improve our understanding how cancer may originate and how cancer cells respond to chemo- or radiation therapy.
Biochemical Investigation Of Ubiquitination By The Fanconi Anaemia Pathway
Funder
National Health and Medical Research Council
Funding Amount
$603,447.00
Summary
Fanconi anaemia is an inherited disorder with greatly elevated risk of leukaemia and cancers. The causal genes are ‘tumour suppressors’ that protect us from cancer by a complex function in repair of damage to our DNA. This study aims to understand how this DNA repair function protects us from cancer, and may influence some forms of new forms of cancer treatment.
New inhibitors of HIV based on cellular enzymes. Over 39 million people are infected with HIV worldwide. However, none of the most highly affected countries have yet reached the peak in AIDS-related illness and death, thus the global impact of HIV/AIDS will get significantly worse, before it gets better.
In Australia, HIV is again on the rise. Ironically, improved treatments that have extended life expectancy will cause the number of HIV infected Australians to rise for many years to come. ....New inhibitors of HIV based on cellular enzymes. Over 39 million people are infected with HIV worldwide. However, none of the most highly affected countries have yet reached the peak in AIDS-related illness and death, thus the global impact of HIV/AIDS will get significantly worse, before it gets better.
In Australia, HIV is again on the rise. Ironically, improved treatments that have extended life expectancy will cause the number of HIV infected Australians to rise for many years to come. Therefore many Australians will suffer from the combined impact of the AIDS illness itself, opportunistic infections, the side-effects of treatment and natural aging. We aim to develop new drugs to combat this disease to help people everywhere lead happier, healthier and more productive lives.Read moreRead less
Sensing atmosphere: Understanding the HNOX-protein gas-sensing capability and how it is affected by heme-oxidation. The project investigates how gas sensing heme-proteins from the novel HNOX (Heme-Nitric Oxide) family are able to discriminate between different gaseous ligands such as O2 and NO and how oxidation of the heme alters this response. The gas-sensing capability of the HNOX proteins is crucial for organisms ranging from bacteria to humans. Thus, understanding of these signalling mechani ....Sensing atmosphere: Understanding the HNOX-protein gas-sensing capability and how it is affected by heme-oxidation. The project investigates how gas sensing heme-proteins from the novel HNOX (Heme-Nitric Oxide) family are able to discriminate between different gaseous ligands such as O2 and NO and how oxidation of the heme alters this response. The gas-sensing capability of the HNOX proteins is crucial for organisms ranging from bacteria to humans. Thus, understanding of these signalling mechanisms will have a strong impact on many scientific fields from the control of pathogen growth to human blood pressure regulation. This collaboration will establish Australian scientists and as world-leading in the field of NO and redox signalling. This development will also be of substantial benefit for the training of the next generation of Australian students and scientists.Read moreRead less
Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a ....Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a form of hierarchical phosphorylation not previously reported. Here we examine hierarchical phosphorylation in rat and human tyrosine hydroxylase and its functional consequence in intact cells. The approaches and methods developed will also be applicable to investigation of hierarchical phosphorylation in other proteins.Read moreRead less
The regulation of signalling molecules in Saccharomyces Cerevisiae by inositol polyphosphate 5-phosphatases. Phosphoinositide signalling molecules regulate the actin cytoskeleton, secretion, vesicular trafficking and cell growth and death. We have identified, cloned and characterised a family of signal terminating enzymes called inositol polyphosphate 5-phosphatases (5-phosphatases) that regulate phosphoinositide signalling molecules. We have cloned and characterised four distinct 5-phosphatases ....The regulation of signalling molecules in Saccharomyces Cerevisiae by inositol polyphosphate 5-phosphatases. Phosphoinositide signalling molecules regulate the actin cytoskeleton, secretion, vesicular trafficking and cell growth and death. We have identified, cloned and characterised a family of signal terminating enzymes called inositol polyphosphate 5-phosphatases (5-phosphatases) that regulate phosphoinositide signalling molecules. We have cloned and characterised four distinct 5-phosphatases in the yeast Saccharomyces Cerevisiae and demonstrated by both deletion and overexpression studies that these enzymes regulate the actin cytoskeleton, endocytosis and secretion. This research proposal aims to investigate the signalling complexes the 5-phosphatases form with specific actin binding and or regulatory proteins, investigate the complex interactions of phosphoinositide lipid phosphatases and the roles they play in regulating secretion from the endoplasmic reticulum and finally characterize a novel 5-phosphatase that we have recently identified. Collectively the outcome of these studies will provide novel information about the functionallly significant signalling pathways regulated by this important enzyme family.Read moreRead less
The role of PtdIns(4,5)P2 in cellular responses in Saccharomyces cerevisiae. This grant application falls under the criteria of frontier technologies in genomics/phenomics and complex systems. We are characterizing a highly conserved network of signaling molecules regulated by complex large families of enzymes that regulate the bending of membranes, and cellular events including cell division in plants, yeast and mammalian cells. We have developed cutting edge novel technologies to localize sign ....The role of PtdIns(4,5)P2 in cellular responses in Saccharomyces cerevisiae. This grant application falls under the criteria of frontier technologies in genomics/phenomics and complex systems. We are characterizing a highly conserved network of signaling molecules regulated by complex large families of enzymes that regulate the bending of membranes, and cellular events including cell division in plants, yeast and mammalian cells. We have developed cutting edge novel technologies to localize signaling on specific intracellular membranes and visualise the role cellular lipids play in forming tubules in cells. This project will result in the presentation of Australian research at international forums and support the training of PhD students.Read moreRead less