Histone H3.3 Dynamics At The Telomere In Pluripotent Embryonic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$571,977.00
Summary
The telomere is required for the protection of the chromosome ends. Telomere loses its repeat during each cell division, so telomere shorthening is one of the mechanisms underlying organismal aging as critically short telomeres induce chromosome instability and cell death. Defective telomeres can also result in genetic diseases and development of cancers. Here, we propose to study the mechanism that operates to ensure continual telomere renewal without senescence in embryonic stem cells.
Regulation And Role Of Transcription At The Centromere.
Funder
National Health and Medical Research Council
Funding Amount
$737,801.00
Summary
Every human cell has 46 chromosomes. Chromosomes are structures that carry genes in all our cells. The centromere is an essential component of a chromosome. It controls the process of cell division, and it ensures the equal division of the duplicated chromosomes. Defects in centromere function can result in various genetic diseases and development of cancers. The structure of the centromere is unique and its properties are determined by an array of proteins and other as yet unknown factors that ....Every human cell has 46 chromosomes. Chromosomes are structures that carry genes in all our cells. The centromere is an essential component of a chromosome. It controls the process of cell division, and it ensures the equal division of the duplicated chromosomes. Defects in centromere function can result in various genetic diseases and development of cancers. The structure of the centromere is unique and its properties are determined by an array of proteins and other as yet unknown factors that bind to it. In our preliminary work, we have demonstrated that a novel non-protein component in the form of RNA (which are expressed products of genes) is essential for the binding of key proteins to the centromere. The presence and importance of such an RNA component has not been previously suspected and represents an exciting new mechanism that help to determine the functional and structural integrity of the centromere. In this project, we propose to study the details of this RNA and to define how this RNA-related mechanism operates to ensure the proper assembly and function of the centromere during cell division.Read moreRead less
Mechanisms By Which Chromatin Modulates Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
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 to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important ....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 to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important function of chromatin is to tightly regulate gene expression which is essential to allow an organism to develop properly. When gene expression is not accurately controlled by chromatin developmental defects or cancer can result from the production of incorrect proteins. To control correct gene expression, highly specific mechanisms must operate in the cell to remove, or modify, nucleosomes at certain genes at a precise time during development. One mechanism that we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the replacement of histones with different specialized forms of these histones (variants). We believe that these histone variants can specifically generate chromosomal domains which could in some cases expose or in other cases hide certain genes and thereby turn them on or off. Employing a new approach, we will study one of these histone variants to discover the role it plays in determining the type of chromosomal domain made and the role of this domain has in turning genes on or off at precise times in early development during the formation of different specialized cell types. This new information may define targets for the prevention of incorrect gene expression during cancer progression or abnormal development.Read moreRead less
A Single Nucleotide Resolution Map Of A Cancer Associated Neochromosome
Funder
National Health and Medical Research Council
Funding Amount
$567,350.00
Summary
Neochromosomes (NCs) are large chromosomes which are not usually found in a normal cell. Well differentiated liposarcoma (WDLPS) is a tumour which is almost universally associated with the presence of NCs. We are using the approach of purifying the NC from a series of WDLPS cell lines, and using new techniques to derive the DNA sequence of the neochromosome. We will use this information to identify the genetic factors on the NC which are involved in the initiation or progression of WDLPS.
Cohesin: Role In Germ Cell Chromosomal Segregation
Funder
National Health and Medical Research Council
Funding Amount
$435,526.00
Summary
At least 10 to 25% of all human fetuses have the wrong number of chromosomes (aneuploidy). Most of these abormal fetuses perish in utero, making it the leading known cause of early pregnancy loss. Aneuploidy is the leading genetic cause of developmental disabilities and mental retardation. Abundant evidence suggests that most of these chromosome abnormalities originate during unequal partitioning of genetic material (chromosomes) in eggs and sperm. The proposed project focuses on two related gen ....At least 10 to 25% of all human fetuses have the wrong number of chromosomes (aneuploidy). Most of these abormal fetuses perish in utero, making it the leading known cause of early pregnancy loss. Aneuploidy is the leading genetic cause of developmental disabilities and mental retardation. Abundant evidence suggests that most of these chromosome abnormalities originate during unequal partitioning of genetic material (chromosomes) in eggs and sperm. The proposed project focuses on two related genes, called Rec8 and Rad21, which we recently discovered in humans and mice. Due to that these genes are essential for chromosome separation in other species and they exists in species as diverse as yeast and humans, they may be responsible for accurate separation of chromosomes in germ cells in mammals. In this proposal, we will determine the role(s) of these molecules in controlling proper chromosome segregation by loss-of-function studies in genetically engineered mice lacking Rec8 and Rad21 genes. By analyzing the chromosomal abnormalities of the cells from these animals, we will gain critical information about the nature of chromosome partitioning disorders in humans.Read moreRead less
Functional Significance Of ATM-dependent Phosphorylation Of Mre11
Funder
National Health and Medical Research Council
Funding Amount
$211,500.00
Summary
The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The in ....The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The intention here is to investigate some of the normal mechanisms of cellular response to radiation and determine why they are deficient in cells from individuals with these rare syndromes. We will focus on a protein, ATM, which is activated by radiation and on one of its substrates Mre11. Both molecules are involved in sensing and transmitting signals from DNA to cell cycle checkpoints. The expected outcome of this study is a greater understanding of the intricate set of signaling pathways that are activated in response to radiation damage. In addition it is expected that a detailed knowledge of these pathways and what goes wrong in specific disease states will be of assistance in understanding risk of developing cancer. Finally this information will also be useful in the design of novel compounds for the prevention and-or treatment of cancer.Read moreRead less
Cohesin Dysfunction: Potential New Route To Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$386,511.00
Summary
This proposal aims to investigate the role of a newly-discovered chromosomal and DNA repair protein, Rad21, in breast cancer. Rad21 is a gene, present in many species and essential for accurate chromosome separation. Based on its' known function in different species, it is conceivable that its' dysfunction could fuel cancer progression by promoting genetic instability, eg. gains or losses of chromosomes, commonly associated with human cancers. No definitive data currently exists as regards the p ....This proposal aims to investigate the role of a newly-discovered chromosomal and DNA repair protein, Rad21, in breast cancer. Rad21 is a gene, present in many species and essential for accurate chromosome separation. Based on its' known function in different species, it is conceivable that its' dysfunction could fuel cancer progression by promoting genetic instability, eg. gains or losses of chromosomes, commonly associated with human cancers. No definitive data currently exists as regards the potential role of this gene in cancer development. This study is thus the first systematic investigation towards understanding the function of this potential cancer-causing gene. Although the proposed study focuses on breast cancers, it could, in principle, apply to other cancer types in which its' overactivity has recently be oberserved. This study could also have implications for the response of humans to radio- and chemo-therapy for cancer treatmentRead moreRead less
The Role Of The Calcineurin Negative Regulator, DSCR1, In Heart Development And Hypertrophy.
Funder
National Health and Medical Research Council
Funding Amount
$431,310.00
Summary
Congenital heart defects in the young and heart disease later in life place a heavy burden on our society in terms of illness, disability and death and are very costly in terms of the health care budget. Failure of heart valve development and holes in the heart, are very common abnormalities occurring in nearly 1 % of all live births. This type of anomaly is also observed in about 44 % of individuals with Down syndrome, which results when individuals carry an extra copy of chromosome 21. Thus, i ....Congenital heart defects in the young and heart disease later in life place a heavy burden on our society in terms of illness, disability and death and are very costly in terms of the health care budget. Failure of heart valve development and holes in the heart, are very common abnormalities occurring in nearly 1 % of all live births. This type of anomaly is also observed in about 44 % of individuals with Down syndrome, which results when individuals carry an extra copy of chromosome 21. Thus, it is likely that a gene located on human chromosome 21 contributes to this pathology and indeed our work on the identification of genes with the potential to cause the heart defect observed in Down syndrome, has led to the discovery of a gene called DSCR1. DSCR1 is a negative regulator of a biological pathway which when disturbed in the heart can lead to developmental heart malformations, similar to the type seen in Down syndrome, and when over stimulated can result in the abnormal growth of the heart seen in humans with hypertension and heart disease. If we are to make rational decisions about the design of potential treatments for heart defects and disease, we firstly need to understand how these biological pathways work and how molecules such as DSCR1 regulate them. We aim to investigate how DSCR1 functions by generating mice that lack the gene, to see what happens when it is missing and mice over expressing the gene to investigate the consequences of elevated levels of DSCR1 analogous to the situation in Down syndrome.Read moreRead less