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
Fish venom as a model system for the molecular evolution of defensive toxins. The key aim of this study is to undertake a thorough investigation of venoms found in distinct fish lineages, including enigmatic species such as venomous and medically important species such as the stonefish. By characterising the biodiversity of toxins found in the venoms of different fish, the evolutionary history of venom in this major vertebrate lineage can be revealed. The investigations proposed here will also d ....Fish venom as a model system for the molecular evolution of defensive toxins. The key aim of this study is to undertake a thorough investigation of venoms found in distinct fish lineages, including enigmatic species such as venomous and medically important species such as the stonefish. By characterising the biodiversity of toxins found in the venoms of different fish, the evolutionary history of venom in this major vertebrate lineage can be revealed. The investigations proposed here will also determine the functional activities of different venoms and their components. This will not only help the understanding of the medical consequences of the annual thousands of fish envenomings but also explore a largely unstudied resource for the discovery of new pharmacological diagnostics and therapeutics.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
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
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
Discovery of pathways to embryogenesis in pathogenic flatworm parasites using microdissection and transcriptomic technologies. The cost to Australia of flatworm parasites to animal production and human health is substantial (hundreds of millions of dollars per year). This research will give new insights into how flatworms reproduce and equip their progeny for survival, providing impetus for new vaccine or drug therapies to be developed. As these pathogens are more significant in Australia's ne ....Discovery of pathways to embryogenesis in pathogenic flatworm parasites using microdissection and transcriptomic technologies. The cost to Australia of flatworm parasites to animal production and human health is substantial (hundreds of millions of dollars per year). This research will give new insights into how flatworms reproduce and equip their progeny for survival, providing impetus for new vaccine or drug therapies to be developed. As these pathogens are more significant in Australia's near neighbours, this project will strengthen Australia's international leadership in this field. Our study will provide, for the first time for any helminth parasite, a freely available genetic database that profiles the gene expression repertoire of individual parasite tissues, a development likely to enhance the international effort in controlling these harmful diseases.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