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 Models Of Cancer Development And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$645,250.00
Summary
We are taking advantage of the powerful genetic tools in fruit flies to study the genetics of cancer. 72% of cancer genes are conserved between humans and fruit flies, making it a particularly suitable system. This project has two main aims: 1- to build tumours in fruit flies in an effort to understand better the individual genetic lesions that contribute to cancer It takes on average 4-7 mutations for a tumour to develop. While many genes associated with cancer have been identified, there are m ....We are taking advantage of the powerful genetic tools in fruit flies to study the genetics of cancer. 72% of cancer genes are conserved between humans and fruit flies, making it a particularly suitable system. This project has two main aims: 1- to build tumours in fruit flies in an effort to understand better the individual genetic lesions that contribute to cancer It takes on average 4-7 mutations for a tumour to develop. While many genes associated with cancer have been identified, there are many more that have not. What is more, it is still not clear precisely what mutations are responsible for a given tumour as tumours contain many genetic lesions most of which are incidental. We have a collection of fruit flies strains that represent various stages of the progress toward cancer development, and we intend to test different genetic combinations of these to determine which combinations result in cancer. 2- to identify a class of genes we have called 'oncogene suppressor genes' which may have the ability to prevent tumours from forming. Recently, it has been discovered that oncogenes may be required for both the INITIATION of tumours and the MAINTENANCE of tumours. This means that suppressing oncogene function may not only prevent tumour formation, but also tumour maintenance - in other words, it may make tumours go away. Thus, oncogene suppressor genes may represent exciting therapeutic targets for the treatment and possibly also prevention of cancer. At this time it is not clear whether oncogenes are generally required for tumour maintenance, or whether this is a property of only one or a few oncogenes. As these experiments are difficult and expensive to conduct in mammalian systems, we have devised simple, rapid tests in fruit flies instead. We plan to use these tests to investigate the effect of 'oncogene suppressor genes' on tumour initiation and maintenance in fruit flies. Ultimately, we believe these genes may represent therapeutic targets.Read moreRead less
Genetic control of plant organ growth. Plants organs, such as leaves and petals, have a distinct size and shape reflecting differences in growth. Despite its importance, very little is known about the mechanisms that regulate growth. The objectives of this proposal are a) to test whether organ growth depends on cell-cell signalling and b) to identifying genes that regulate growth, and to characterize their molecular function.
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.
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
Marsupial germ cells and genes. Germ cells are the most fascinating cells in the body, since theirs is the unique responsibility for transmitting life from generation to generation. Studies in mice have suggested that position in the embryo determines their origin, but the early embryology of the mouse is so different from that of other mammals that the events need confirming and extending in another species. The simplified embryology of the tammar wallaby makes it ideal for studying one of the ....Marsupial germ cells and genes. Germ cells are the most fascinating cells in the body, since theirs is the unique responsibility for transmitting life from generation to generation. Studies in mice have suggested that position in the embryo determines their origin, but the early embryology of the mouse is so different from that of other mammals that the events need confirming and extending in another species. The simplified embryology of the tammar wallaby makes it ideal for studying one of the most fundamental questions in the whole of biology: what is the basis for the primal distinction between sex and soma?Read moreRead less
How does the unilaminar blastocyst form an embryo? Marsupials are synonymous with Australia and they are scientifically amazing. An understanding how the single-layered marsupial blastocyst cells are directed to form the complex organisation of an embryo would help us understand the biology underlying the developmental potential of all cells. Understanding these processes is not only of great fundamental interest to developmental biology but also for the development of embryonic stem cell lines. ....How does the unilaminar blastocyst form an embryo? Marsupials are synonymous with Australia and they are scientifically amazing. An understanding how the single-layered marsupial blastocyst cells are directed to form the complex organisation of an embryo would help us understand the biology underlying the developmental potential of all cells. Understanding these processes is not only of great fundamental interest to developmental biology but also for the development of embryonic stem cell lines. This research will continue Australia's high profile in reproductive biology using one of our iconic native mammals. A greater understanding of marsupial reproduction will also contribute to management of our threatened marsupial populations.Read moreRead less
Taming the intruders: the domestication of Tigger transposable elements in mammals. It has become apparent that most of the DNA that makes us what we are is actually comprised of the remnants of invading parasitic DNA acquired over time. A continual battle exists between host which tries to silence or remove this DNA, and the parasite that tries to multiply and spread. We are currently investigating an intriguing aspect of this process that involves host genomes 'domesticating' parasitic DNA to ....Taming the intruders: the domestication of Tigger transposable elements in mammals. It has become apparent that most of the DNA that makes us what we are is actually comprised of the remnants of invading parasitic DNA acquired over time. A continual battle exists between host which tries to silence or remove this DNA, and the parasite that tries to multiply and spread. We are currently investigating an intriguing aspect of this process that involves host genomes 'domesticating' parasitic DNA to provide novel functions, thereby facilitating the evolution of specific characteristics within species.Read moreRead less
Identification of nuclear reprogramming factors in oocyte cytoplasm. The mature oocyte contains dominant factors that are capable of erasing tissue specific gene expression profiles of somatic cells. These reprogramming factors would be valuable for dedifferentiation of cells and for nuclear transfer in animal cloning. The research involves determination of reprogramming factors present in active cytoplasm following enucleation of the germinal vesicle, blockage of transcription and translation, ....Identification of nuclear reprogramming factors in oocyte cytoplasm. The mature oocyte contains dominant factors that are capable of erasing tissue specific gene expression profiles of somatic cells. These reprogramming factors would be valuable for dedifferentiation of cells and for nuclear transfer in animal cloning. The research involves determination of reprogramming factors present in active cytoplasm following enucleation of the germinal vesicle, blockage of transcription and translation, and timed cultures. The assays will involve maintenance of reprogramming ability and erasure of somatic gene transcription. By subtractive elimination the function of isolated proteins which are involved in reprogramming will be identified for potential recombinant production.Read moreRead less