Senataxin, A Novel Protein Involved In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. T ....The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. This disorder is called ataxia with oculomotor apraxia type 2 or AOA2. This condition develops in the teenage to early twenties and as the name suggests is characterised by loss of control of gait together with difficulties of eye movement. It is due to reduced function of a particular region of the brain called the cerebellum responsible for controlling movement. We have initial data suggesting that cells from these patients are very sensitive to environmental chemicals and their capacity to carry out repair of damage to DNA is compromised. We will investigate the nature of the defect at the molecular level and establish the function of the protein defective in this syndrome. This information will be important to determining specific therapies for AOA2 patients and may also have relevance to other neurodegenerative disorders.Read moreRead less
Functions Of A Novel Conserved DNA Damage Response Protein Family In Telomere Stability
Funder
National Health and Medical Research Council
Funding Amount
$282,825.00
Summary
The free DNA ends of chromosomes, termed telomeres, generally resemble broken DNA. Because broken DNA is a major contributing factor to the onset of cancer, cells try to fix broken ends. However, in case of telomeres, such repair processes have to be prevented because otherwise different chromosomes would fuse with each other. Fused chromosomes are very fragile and cannot be evenly distributed between dividing cells, and are therefore another important trigger of cancer development. Therefore, c ....The free DNA ends of chromosomes, termed telomeres, generally resemble broken DNA. Because broken DNA is a major contributing factor to the onset of cancer, cells try to fix broken ends. However, in case of telomeres, such repair processes have to be prevented because otherwise different chromosomes would fuse with each other. Fused chromosomes are very fragile and cannot be evenly distributed between dividing cells, and are therefore another important trigger of cancer development. Therefore, chromosome ends are covered by a cap, which hides them from the DNA damage response machinery. From these considerations it is clear that there are close connections between the cellular DNA damage response and chromosome ends. Moreover, recently it has become clear that DNA damage proteins are also required to stop normal cells from growing, a process termed senescence. Senescence is a consequence of shortened chromosome ends, and does not occur in cancer cells. Altogether, it is clear that DNA breaks and senescence are two of the major questions for our understanding of cancer development. We have identified a novel conserved protein family that is involved in the response to DNA damage in yeast and humans. In addition, the yeast Mdt1 protein is a very sensitive indicator of changes in the telomere cap. Absence of proteins that organise the cap leads to the addition of several phosphate groups to the Mdt1 protein. We propose that phosphate-coupled Mdt1 prevents chromosome ends from fusion with each other, or from fusing with broken DNA ends after widespread damage. As a consequence, cells that have mild cap defects die at an >1000-fold increased rate in response to DNA damage when they also lack Mdt1. As part of this application we want to find out the precise mechanism by which Mdt1 stabilises chromosome ends, and test our hypothesis that the corresponding human protein termed ASCIZ also has similar functions in protecting chromosome ends.Read moreRead less
Phasevarions of Haemophilus influenzae: mechanisms and origins of a novel epigenetic system controlling coordinated random switching in expression of multiple genes. Central to the utilisation of biological information is our ability to identify and interpret DNA sequence information from genomes. In bacteria that cause disease, these investigations can identify key aspects of the infectious process or potential components of vaccines or new targets for antibiotics. Our recent work has identifie ....Phasevarions of Haemophilus influenzae: mechanisms and origins of a novel epigenetic system controlling coordinated random switching in expression of multiple genes. Central to the utilisation of biological information is our ability to identify and interpret DNA sequence information from genomes. In bacteria that cause disease, these investigations can identify key aspects of the infectious process or potential components of vaccines or new targets for antibiotics. Our recent work has identified a new genetic system, the 'phasevarion', that mediates random expression of multiple genes. The proposed research aims to advance our understanding of gene expression at the most basic level, revealing how bacteria generate diverse populations to evade environmental and immune stresses, and facilitating improved interpretation and use of DNA sequences for researchers and industry in this field.Read moreRead less
Sex-specific epigenetic atlas across lifespan . This project aims to uncover sex-specific molecular marks that either predict or mediate healthy ageing across multiple tissues in humans. This project expects to generate new knowledge of cellular heterogeneity and epigenetic control of phenotype and healthy ageing. Further, we anticipate to uncover age-associated changes that differ between males and females, an area of chronic research under representation. These outcomes will lead to a comprehe ....Sex-specific epigenetic atlas across lifespan . This project aims to uncover sex-specific molecular marks that either predict or mediate healthy ageing across multiple tissues in humans. This project expects to generate new knowledge of cellular heterogeneity and epigenetic control of phenotype and healthy ageing. Further, we anticipate to uncover age-associated changes that differ between males and females, an area of chronic research under representation. These outcomes will lead to a comprehensive understanding of fundamental biological processes across lifespan, and our development of an open access atlas will underpin evidence-based personalised health strategies to keep Australians healthier for longer. Read moreRead less
The Evolution and Diversification of Apicomplexan Cell Invasion Mechanisms. Insights gained through this project, about the mechanisms of cell invasion in Apicomplexan parasites, will have far reaching implications for a number of parasites of great significance to humans and animals. Since host cell invasion is a key step in the parasite lifecycle, proteins identified here will be prime targets for novel drugs that prevent invasion or antigens that can be used as vaccines. This will be importan ....The Evolution and Diversification of Apicomplexan Cell Invasion Mechanisms. Insights gained through this project, about the mechanisms of cell invasion in Apicomplexan parasites, will have far reaching implications for a number of parasites of great significance to humans and animals. Since host cell invasion is a key step in the parasite lifecycle, proteins identified here will be prime targets for novel drugs that prevent invasion or antigens that can be used as vaccines. This will be important for developing new control strategies for diseases of global significance such as malaria or toxoplasmosis, as well as those of national importance to the food industry of Australia, including diseases like babesiosis and coccidiosis that cause significant economic loss to the livestock and poultry industries each year.Read moreRead less
Discovering genes and mechanisms regulating immune responses. The Fellowship will retain and expand a pioneering Australian research program, and attract to Australia major international investment and technology linkages, making use of the DNA sequence of humans and other mammals to advance understanding of immunity and infection control in public health, agriculture and industry. The program will build on Australia's pre-eminent research strengths in the field of immunity and infection, and w ....Discovering genes and mechanisms regulating immune responses. The Fellowship will retain and expand a pioneering Australian research program, and attract to Australia major international investment and technology linkages, making use of the DNA sequence of humans and other mammals to advance understanding of immunity and infection control in public health, agriculture and industry. The program will build on Australia's pre-eminent research strengths in the field of immunity and infection, and will create new knowledge and resources to improve human and animal health through vaccines, pharmaceuticals and public health policy. Read moreRead less
Pre-clinical evaluation of snake venom proteins with therapeutic potential. Australia harbors some of the most toxic snakes in the world. Their venoms contain a range of substances that are designed to rapidly immobilize and kill their prey. These include agents that lead to enhanced blood clotting; excess bleeding. We have isolated and characterized a large number of the components involved over the last several years. The aim here is to carry out pre-clinical trials in animal models to test th ....Pre-clinical evaluation of snake venom proteins with therapeutic potential. Australia harbors some of the most toxic snakes in the world. Their venoms contain a range of substances that are designed to rapidly immobilize and kill their prey. These include agents that lead to enhanced blood clotting; excess bleeding. We have isolated and characterized a large number of the components involved over the last several years. The aim here is to carry out pre-clinical trials in animal models to test the efficacy of three proteins as anti-bleeding agents and investigate several other novel components. The ultimate outcome will be the development of novel drugs that will have application in the treatment of human disorders. Read moreRead less
eGenomics - Next generation biomonitoring of threatened species. DNA is the molecule of life and exists everywhere in the environment as a largely untapped source of information on evolution, biodiversity, and ecosystem health. Our overriding aim is to start mining that information to benefit threatened species. Based on optimized ancient DNA methods, powerful sequencing technology, whole genome analyses, and RNA profiling, we present a novel and holistic framework for genetic biomonitoring. In ....eGenomics - Next generation biomonitoring of threatened species. DNA is the molecule of life and exists everywhere in the environment as a largely untapped source of information on evolution, biodiversity, and ecosystem health. Our overriding aim is to start mining that information to benefit threatened species. Based on optimized ancient DNA methods, powerful sequencing technology, whole genome analyses, and RNA profiling, we present a novel and holistic framework for genetic biomonitoring. In two parallel model systems we will study corals and reptiles to improve environmental detection while simultaneously obtaining information on their population health. This will foster more efficient conservation of endangered species that are of tremendous importance to our marine and terrestrial ecosystems.Read moreRead less
The molecular evolution of wings in flightless birds. The flightless Australian emu and New Zealand kiwi have small wings, while the extinct moa had none at all. This project will identify the genetic changes that have lead to wing reduction and loss in flightless birds. The results will shed light on the genetic control of forelimb development and how it has evolved.
Echoes of the earliest Homo sapiens movement out of Africa. The "Out of Africa" and "Multiregional Evolution" theories have proposed sharply different accounts for the origins of our species Homo sapiens. These have converged on opposite readings of the Australian human fossil record. Recent perspectives resulting from research on Pleistocene Australian mitochondrial DNA, and by osteologists on early Homo sapiens remains in Africa and Israel, hint at a chapter, as yet unwritten, in our species' ....Echoes of the earliest Homo sapiens movement out of Africa. The "Out of Africa" and "Multiregional Evolution" theories have proposed sharply different accounts for the origins of our species Homo sapiens. These have converged on opposite readings of the Australian human fossil record. Recent perspectives resulting from research on Pleistocene Australian mitochondrial DNA, and by osteologists on early Homo sapiens remains in Africa and Israel, hint at a chapter, as yet unwritten, in our species' Late Pleistocene dispersal from Africa. This project's collaborative research on fossils from Sri Lanka and Australasia will explore and test the implications for the colonisation history of the Indian Ocean region.Read moreRead less