One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA) can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining chromosome stability can lead to aneuploidy (cells with an abnormal number o ....One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA) can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining chromosome stability can lead to aneuploidy (cells with an abnormal number of chromosomes), a feature exhibited by many forms of cancer. This packaging of genomic DNA that produces a chromosome is achieved by a complex scheme of folding. At the first level, DNA is first wrapped around a mixture of proteins (called histones) to form a complete unit known as a nucleosome. About 30 million of these building blocks are required in every human cell to compact our DNA. Higher, more complicated levels of organization exist in which a linear array of nucleosomes fold to various extents to form distinct functional and structural domains. Importantly, specialised chromosomal domains, like the telomere and centromere, are assembled that keep the ends of the chromosomes stable and enable a chromosome to copy itself every time our cells divide and grow, respectively. How a chromosome is divided into these different compartments remains a mystery. This investigation will show that a key cellular mechanism that determines how the chromosome is organised into stable domains is by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . These histone variants control the way a linear array of nucleosomes fold into complex three-dimensional structures to perform a specialised function. This fundamental research will provide important new information on how chromosomes become unstable in cancer. It will also enable new strategies, which stabilise the chromosome, to be explored.Read moreRead less
Structure And Function Of The Alternative Splicing Factor ZNF265
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
Now that the human genome has been sequenced, we can see that a human being is defined bye approximately 30000 genes. One of the biggest surprises to come from this work was that the number of genes was significantly smaller than many predicted. Similar surprise was registered at the discovery that the genome of the fruit fly actually contained fewer genes than that of the model worm, Caenorhabditis elegans. Part of the explanation for these apparent discrepencies lies in the phenomenon known as ....Now that the human genome has been sequenced, we can see that a human being is defined bye approximately 30000 genes. One of the biggest surprises to come from this work was that the number of genes was significantly smaller than many predicted. Similar surprise was registered at the discovery that the genome of the fruit fly actually contained fewer genes than that of the model worm, Caenorhabditis elegans. Part of the explanation for these apparent discrepencies lies in the phenomenon known as gene splicing, whereby one gene can actually give rise to many different isoforms of the same protein. These different isoforms can have different structures and-or functions, and dramatically increase the complexity that it is possible for an organism to achieve with a given number of genes. The process of splicing is very intricate, requiring precise control to allow an organism to develop normally. Many human genetic diseases are known to arise from problems with splicing. However, our understanding of the mechanisms of splicing is rather incomplete. This proposal aims to improve our understanding of the splicing process through a range of biophysical and molecular biological approaches. This information should prove useful in understanding human development and disease.Read moreRead less
The Role Of Heterochromatin In Regulating Cellular Proliferation And Development
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the ....Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein (histones) to form a structure known as chromatin. It has become clear that the chromatin structure encompassing a gene is the critical factor that determines whether a gene is expressed or silenced. We propose that developmental and cell-type specific mechanisms operate in a cell to assemble genes into highly specialised chromatin structures that permit (euchromatin) or restrict (heterochromatin) gene expression. In other words, the genome of each different cell type is organised into a unique and dynamic chromatin pattern and this pattern determines the gene expression profile. This investigation will show that the critical cellular mechanism that determines the chromatin pattern for a particular cell type is the regulation of the quantity and quality of heterochromatin. Specifically, we will demonstrate that this is achieved, in a developmental and tissue specific manner, by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . In addition, we will expose a new mechanism of how heterochromatin formation controls the rate of cellular proliferation. This information will provide new insights into how gene expression profiles are established at precise times in early development, and offer a new strategy to inhibit the proliferation of cancer cells.Read moreRead less
Structural Characterisation Of A Natural Inhibitor Of Sporulation Bound To Its Histidine Kinase Target
Funder
National Health and Medical Research Council
Funding Amount
$261,000.00
Summary
Many bacteria, including some which are virulent pathogens such as anthrax (Bacillus anthracis), are able to enter a dormant state by forming spores (sporulation). These spores are extremely robust and may persist in the environment buried in the soil for example for hundreds of years. The initiation of sporulation occurs in response to changes in the cellular and environmental conditions which threaten the free replicating existence of the bacterium. The process of sporulation is controlled at ....Many bacteria, including some which are virulent pathogens such as anthrax (Bacillus anthracis), are able to enter a dormant state by forming spores (sporulation). These spores are extremely robust and may persist in the environment buried in the soil for example for hundreds of years. The initiation of sporulation occurs in response to changes in the cellular and environmental conditions which threaten the free replicating existence of the bacterium. The process of sporulation is controlled at the molecular level by a complex signaling relay. It is of course vital for the existence of the organism that control of sporulation is tightly regulated - preventing the onset of spore-formation in any but the desired circumstances. We aim to determine the three-dimensional structures of the molecules involved in this regulated process and how, by interacting with each other, they can pass on the signal to the bacterium to either start or stop the spore forming process. Ultimately, the results of this work might lead to antibacterial agents which could be used to control particularly dangerous strains of bacteria.Read moreRead less
The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death s ....The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death signals. Recent studies have demonstrated that the mechanisms of signal transduction through Fas and TNFR1 differ significantly, however, they both require the adaptor protein FADD to induce apoptosis. In this study we will elucidate the molecular basis of the interactions between FADD and its binding partners using biochemical and biophysical studies. This research will improve our understanding of death receptor-induced apoptosis and the differences in signalling mechanisms. A detailed knowledge of these aspects of death receptor signalling is of significance because they represent critical regulatory steps that could be useful for targeted interventions.Read moreRead less