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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
Genetic Variation Of Mitochondrial Complex I: Its Role In Rare And Common Diseases
Funder
National Health and Medical Research Council
Funding Amount
$628,415.00
Summary
Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the uniqu ....Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This grant focuses on the most common energy generation disorder, known as Complex I deficiency. Complex I requires 46 separate components to be assembled together in order to work properly, but mutations in the 46 genes encoding these components only seem to explain disease in about half of all patients. Our aim is to identify new disease genes and to determine whether some patients have mutations in two different genes that interact to cause disease, rather than in a single gene. We will use a number of methods to pinpoint where in the genome the causative genes are located and then home in on the exact changes in the genes that cause disease. Identifying these genes will allow us to improve future diagnosis and prevention of mitochondrial disease. We will also generate mice in which one of the Complex I genes has been knocked out. These mice will allow us to better understand the basic disease mechanisms that link gene changes to disease. Understanding the basic biology may allow us to develop new methods of treatment. The mouse models will also be useful for trialling new treatments and for investigating the role of milder mitochondrial problems in common diseases such as diabetes and Parkinson disease. Any new treatments could potentially have wide application.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
Unravelling the biochemical fingerprint of Australian native plants for sustainable farm forestry and other applications. Dryland salinity is an issue of national significance due to its impact on primary industries which contribute billions of dollars to our economy. However, millions of hectares of arable land are now affected by salinity, with devastating effects on crops, native plants, water quality and wildlife. This project works with the rural community and exploits the unique gene poo ....Unravelling the biochemical fingerprint of Australian native plants for sustainable farm forestry and other applications. Dryland salinity is an issue of national significance due to its impact on primary industries which contribute billions of dollars to our economy. However, millions of hectares of arable land are now affected by salinity, with devastating effects on crops, native plants, water quality and wildlife. This project works with the rural community and exploits the unique gene pool of certain Australian salinity-tolerant plants for environmental benefits (revegetation, salinity control) and simultaneous economic returns through using these for timber and perennial fodder. The project thus addresses the national priorities of preventing the expansion of salinity, putting it to sustainable uses and preserving biodiversity.Read moreRead less
Humane Chemical Methods for Population Management of Highly Valued Large Mammals. In many countries valued wild and feral animals are nonetheless too numerous. Their population numbers must be controlled through fertility. Examples are koalas in Australia, deer and seals in North America, cattle in India and dogs in Thailand. We aim to develop benign implants for castration based upon the gonadotrophin releasing hormone (GnRH). These implants are easily administered. The outcomes will be to ....Humane Chemical Methods for Population Management of Highly Valued Large Mammals. In many countries valued wild and feral animals are nonetheless too numerous. Their population numbers must be controlled through fertility. Examples are koalas in Australia, deer and seals in North America, cattle in India and dogs in Thailand. We aim to develop benign implants for castration based upon the gonadotrophin releasing hormone (GnRH). These implants are easily administered. The outcomes will be to protect Australia's ?green? image , worldwide market opportunities for the Australian companies involved in this application and valuable intellectual property for Macquarie. The methodology will in time allow us to apply it to the treatment of cancer.Read moreRead less
Genomic Basis of Resistance to Poisoning by Sodium Fluoroacetate (Compound 1080) in Australian Wildlife. In Australia agricultural conservation activities worth billions of dollars are protected by using sodium fluoroacetate (1080) against pest animals. Target species are Australian rabbits and foxes and New Zealand brushtail possums. Prolonged use of biocontrol agents causes genetic resistance. This occurs naturally in Western Australia in native animals living in areas with high levels of 1080 ....Genomic Basis of Resistance to Poisoning by Sodium Fluoroacetate (Compound 1080) in Australian Wildlife. In Australia agricultural conservation activities worth billions of dollars are protected by using sodium fluoroacetate (1080) against pest animals. Target species are Australian rabbits and foxes and New Zealand brushtail possums. Prolonged use of biocontrol agents causes genetic resistance. This occurs naturally in Western Australia in native animals living in areas with high levels of 1080 in native plants. As part of the Kangaroo Genome project our aim is to discover the genomic basis of this resistance. The outcomes will be improved ability to manage pest animal populations and understanding of the evolution of plant-animal interactions.Read moreRead less
Optimising plant populations for ecological restoration and resilience. When choosing individual plants for restoration populations, there is potentially a trade-off between maximising genetic diversity (‘adaptability’) and selection for desirable properties (‘adaptation’). This project aims to develop pioneering methods to quantify this trade-off, and facilitate the design of optimised populations, with a focus on two Australian rainforest trees that are being impacted by myrtle rust infection: ....Optimising plant populations for ecological restoration and resilience. When choosing individual plants for restoration populations, there is potentially a trade-off between maximising genetic diversity (‘adaptability’) and selection for desirable properties (‘adaptation’). This project aims to develop pioneering methods to quantify this trade-off, and facilitate the design of optimised populations, with a focus on two Australian rainforest trees that are being impacted by myrtle rust infection: Rhodamnia argentea and Rhodamnia rubescens. By studying the genetic variation in each species, and how this relates to myrtle rust resistance and climate, this project aims to design populations that are genetically diverse, maximally resistant to myrtle rust, and adapted to future climate.Read moreRead less
The genomics of adaptation to environmental change in an ecologically important non-model aquatic organism. Understanding whether natural populations will be able to adapt to rapid environmental change is a major research priority in the twenty-first-century. This project will answer fundamental questions about adaptation and will contribute towards the sustainable management of both aquatic biodiversity and water resources in Australia.
Dispersal and persistence of large-seeded forest species under global environmental change. This project investigates how decline of a key seed disperser, the emu, due to global environmental change (fragmentation, fire regime change, human population growth, climate change) affects the persistence and migration potential of endemic SW Australian forest plant species. Results will inform approaches to ecosystem management and conservation