Spatial Arrangement And Three-dimensional Structure Of Human Centromeres
Funder
National Health and Medical Research Council
Funding Amount
$283,000.00
Summary
Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tight ....Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tightly at the centromere. We also want to find out why centromeres locate in certain regions of the nucleus, because this may influence how the centromere works and how they regulate genes. Human centromeres come in many sizes and forms; by looking at a wide range of human centromeres, common structural and spatial properties will emerge. We have discovered very small centromeres - neocentromeres - which are much easier to study than other centromeres. We have used these centromeres to construct human minichromosomes, which we believe represent the main, all-human way forward to treat people with gene therapy. One way to help us achieve our aims is to stretch out centromeres in a controlled way to make it easier to visualise their structure. Our tools will be antibodies, fluorescently-labelled proteins and high resolution microscopes. These include an electron microscope, and microscopes that can produce optical sections and in turn a 3D image. One of these is the confocal laser scanning microscope; the other involves removal of out-of-focus light from images using deconvolution software to achieve the same goal. We will detect different centromere proteins with different fluorochromes for fluorescence microscopes and different sizes of gold particles for the electron microscope. Using these microscopes we have already been able to find out where one of our neocentromeres is located within the nucleus. We have also started to look at centromeres with the electron microscope.Read moreRead less
Essential Roles Of RNA Polymerase II Transcription And DNA Damage Response Pathway In The Maintenance Of Centromere Chromatin Assembly
Funder
National Health and Medical Research Council
Funding Amount
$601,224.00
Summary
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growt ....A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growth and cancer development.Read moreRead less
Epigenetic Regulation Of Core Centromere CENP-A Chromatin Integrity
Funder
National Health and Medical Research Council
Funding Amount
$318,284.00
Summary
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growt ....A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growth and cancer development.Read moreRead less
The Organisation Of The Chromosome Into Distinct Epigenetic Domains And Its Link With Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$521,591.00
Summary
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 . This fundamental research will provide important new information on how chromosomes become unstable in cancer.
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
Investigating The Role Of Novel Heterochromatin And Centromere Proteins In Chromosome Segregation
Funder
National Health and Medical Research Council
Funding Amount
$522,896.00
Summary
The equal division of genetic material during cell division is essential so that genetic material is not lost or gained. This process is controlled by a complex array of proteins that replicate the genome, maintain its structural integrity, and equally distribute one copy to each daughter cell. This research aims to study the functions of newly identified proteins required for this process in a single cell yeast model-system and in human and mouse 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