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
New approaches for screening cereal germplasm for enhanced microbial pathogen resistance and desirable grain texture. The trait of grain hardness (texture) is of significance to the Australian infrastructure, as exports of hard wheat contribute over 5 billion dollars per year on average to the national economy and hard wheats are also important for domestic usage. The genes responsible for grain texture also impart resistance to bacterial and fungal pathogens which can cause extensive damage. ....New approaches for screening cereal germplasm for enhanced microbial pathogen resistance and desirable grain texture. The trait of grain hardness (texture) is of significance to the Australian infrastructure, as exports of hard wheat contribute over 5 billion dollars per year on average to the national economy and hard wheats are also important for domestic usage. The genes responsible for grain texture also impart resistance to bacterial and fungal pathogens which can cause extensive damage. However, the Australian gene pool has very limited genetic diversity in grain textures and thus possibly in pathogen resistance. The project will work out the science behind these two traits and identify lines with new variants of textures and pathogen resistances, thus greatly benefiting the national infrastructure and local primary industries.Read moreRead less
The Cytochrome P450 Gene Super-family in Drosophila melanogaster; Gene Function and Insecticide Resistance. The cytochrome P450 (Cyp) gene super-family is represented by over 90 sequences in the genome of the vinegar fly, Drosophila melanogaster. To date, four Cyp genes are found to be involved in insecticide resistance. The function of the majority of Cyp genes is unknown. This project will investigate the function and regulation of D. melanogaster Cyp genes, linking the fly's genotype to its ....The Cytochrome P450 Gene Super-family in Drosophila melanogaster; Gene Function and Insecticide Resistance. The cytochrome P450 (Cyp) gene super-family is represented by over 90 sequences in the genome of the vinegar fly, Drosophila melanogaster. To date, four Cyp genes are found to be involved in insecticide resistance. The function of the majority of Cyp genes is unknown. This project will investigate the function and regulation of D. melanogaster Cyp genes, linking the fly's genotype to its phenotype. By studying the effects of Cyp genes on fly survival, Cyp gene expression and regulation, and expressing selected Cyp genes in a yeast expression system, we will enhance our understanding of Cyp gene function and evolution.Read moreRead less
ARC Centre of Excellence in Biotechnology and Development. The Centre will create a multidisciplinary research team focusing on the molecular mechanisms that drive the specification and differentiation of male germ cells. This research will improve our fundamental understanding of how complex regulatory networks control the expression of a complex phenotype, the spermatozoon. It will also create a platform of knowledge from which we can stimulate the growth of the Australian Biotechnology indust ....ARC Centre of Excellence in Biotechnology and Development. The Centre will create a multidisciplinary research team focusing on the molecular mechanisms that drive the specification and differentiation of male germ cells. This research will improve our fundamental understanding of how complex regulatory networks control the expression of a complex phenotype, the spermatozoon. It will also create a platform of knowledge from which we can stimulate the growth of the Australian Biotechnology industry, the protection of the Australian Environment and the well-being of the Australian people. Key issues for this Centre include testicular cancer, male infertility, contraception, pest animal control, environmental impacts on human health and gene pharming.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
Insect host/vector genetic responses to rhabdovirus infection. Rhabdoviruses cause important diseases in humans, animals and plants. These viruses are transmitted by insect vectors in which they persist and propagate, an intimate and specific association. Insect-rhabdovirus interactions will be studied at the molecular level using a planthopper-maize rhabdovirus model. Insect genes specifically induced by rhabdovirus infection as well as the viral genes themselves will be identified and characte ....Insect host/vector genetic responses to rhabdovirus infection. Rhabdoviruses cause important diseases in humans, animals and plants. These viruses are transmitted by insect vectors in which they persist and propagate, an intimate and specific association. Insect-rhabdovirus interactions will be studied at the molecular level using a planthopper-maize rhabdovirus model. Insect genes specifically induced by rhabdovirus infection as well as the viral genes themselves will be identified and characterized using genomics and bioinformatics tools. We will extend the same approaches to a comparative analysis of these planthopper genes with other insect-rhabdovirus systems under investigation in our institutes. Identification of viral genes expressed in insects, the insect genes that respond to virus infection, and interpretation of the roles of these genes in insects, may indicate new opportunities to control serious plant and animal diseases through control of virus transmission.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
Identification of Traits and Function by Genomic Matching. Differences between individuals are largely inherited and therefore encoded within the DNA. The challenge is to develop practical means of detecting these differences irrespective of whether they are observable as a phenotype.
Here we focus on livestock. For example, most Australian cattle are horned rather than polled. The inheritance is relatively simple but there is still no DNA test to detect the recessive horning gene.
T ....Identification of Traits and Function by Genomic Matching. Differences between individuals are largely inherited and therefore encoded within the DNA. The challenge is to develop practical means of detecting these differences irrespective of whether they are observable as a phenotype.
Here we focus on livestock. For example, most Australian cattle are horned rather than polled. The inheritance is relatively simple but there is still no DNA test to detect the recessive horning gene.
The genomic matching technique is an in-house patented procedure for identifying such DNA differences. If successful, our test will assist industry to eliminate horning and thereby painful dehorning whilst reducing damage to workers and product.
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The control of chromosome division during female meiosis. Mammalian eggs are stored life-long and finally mature in the hours before ovulation. This project examines how the chromosomes in the egg are separated properly so as to produce a mature egg capable of being fertilized by a sperm. Often in eggs chromosome division is imprecisely executed, and this project will help us understand why this occurs.