Title: Mechanisms of telomere cap function DNA within each cell is packaged into chromosomes, the ends of which are called telomeres. The DNA in telomeres consists of 6 letters of the genetic code, TTAGGG, repeated hundreds or thousands of times. A number of proteins, including some that have not yet been identified, bind to this DNA and form a cap structure to protect the chromosome ends. Telomeres need to be able to serve a number of specialised functions, including protection against enzymes ....Title: Mechanisms of telomere cap function DNA within each cell is packaged into chromosomes, the ends of which are called telomeres. The DNA in telomeres consists of 6 letters of the genetic code, TTAGGG, repeated hundreds or thousands of times. A number of proteins, including some that have not yet been identified, bind to this DNA and form a cap structure to protect the chromosome ends. Telomeres need to be able to serve a number of specialised functions, including protection against enzymes that degrade DNA ends, and preventing chromosome ends from sticking to each other, while allowing access for DNA copying enzymes when the cell is preparing to divide into two. In some inherited conditions, the telomeres fail to perform these functions efficiently, leading to cellular dysfunction, premature ageing of cells, and ultimately disease. In some types of cells, especially cancer cells, the telomeres also permit the access of molecular machinery that lengthens the telomeres. There are at least two types of lengthening processes, one of which is a complex enzyme called telomerase, and the other an incompletely characterised process that we discovered and named Alternative Lengthening of Telomeres (ALT). In some circumstances, the telomeres of cancer cells appear to be able to discriminate between telomerase and ALT, and to allow one mechanism to operate but not the other. We will analyse how telomeres perform their capping functions, and will determine the differences between normal and cancer cells in this regard. This will lay the groundwork for efforts to develop new forms of cancer treatment that act by preventing cancer cells from lengthening their telomeres.Read moreRead less
Molecular Mechanisms And Control Of Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell fr ....Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell from dividing any further, and acts as a very potent barrier to the cell becoming cancerous. Some normal cells are not subject to this inexorable telomere shortening: these are the germ cells in the testis and ovary, that are responsible for passing on genetic material to the next generation. Such cells express an enzyme, telomerase, which is able to synthesise new telomeric DNA to replace that lost during cell division. 85% of human cancers are also able to prevent shortening of their telomeres - and thus have breached the barrier that normally prevents unlimited cell proliferation - via telomerase activity. Therefore, if drugs that inhibit telomerase can be developed they may be a very useful new form of cancer treatment. We have found, however, that some cancers are able to prevent telomere shortening by a process that does not involve telomerase, and which we refer to as Alternative Lengthening of Telomeres (ALT). One practical implication of this finding for the design of new cancer treatments is that telomerase inhibitors will need to be used in combination with ALT inhibitors. In this study, we will determine A. how normal cells keep the ALT mechanism permanently shut down and B. the molecular details of the ALT mechanism itself. An understanding of these processes may ultimately contribute to the development of novel cancer treatments that disrupt the ability of cancer cells to divide an unlimited number of times.Read moreRead less
DNA methylation-based diagnosis of cancer and identification of novel therapeutic targets. In our aging society, cancer represents a severe economic and quality-of-life threat. DNA methylation switches genes off, and recently, it was shown that defects in DNA methylation contribute to human diseases including cancer. This project will identify defects in DNA methylation associated with cancer. Identifying these defects will enable us to design non-invasive, early diagnostic tests for cancer on b ....DNA methylation-based diagnosis of cancer and identification of novel therapeutic targets. In our aging society, cancer represents a severe economic and quality-of-life threat. DNA methylation switches genes off, and recently, it was shown that defects in DNA methylation contribute to human diseases including cancer. This project will identify defects in DNA methylation associated with cancer. Identifying these defects will enable us to design non-invasive, early diagnostic tests for cancer on blood or bodily excretions, and to pursue novel therapeutic approaches for treating cancer. The expected outcomes would generate exports to markets in the USA and Europe and replace imports of drugs and technology to treat cancer.Read moreRead less
Identification of genes regulating breast cancer progression and metastasis. Breast cancer is the most common cause of cancer-related death in women in Australia. Although the treatments have improved over the last thirty years, many women still die from relapse of the disease. Our goal is to identify genes involved in the regulation of breast cancer progression and metastasis. This may lead to the discovery of druggable molecules for better targeted therapies for patients.
Communication skills training for oncology health care professionals working with culturally and linguistically diverse patients. The project will develop and evaluate two novel training programs designed to equip health professionals to communicate with cancer patients from different cultures. It is expected that the programs will improve trainees’ ability to communicate in a culturally sensitive way.
Cellular And Molecular Determinants Of Preleukaemic And Leukaemic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$292,635.00
Summary
It has recently become evident that the formation, growth and relapse of many cancers is driven by a rare population of cancer stem cells (CSCs) that have the unique ability to propagate new tumours and are highly resistant to current therapies. However, which normal cells are transformed into CSCs is not known. We will take a potent cancer gene found in leukaemia, and switch it on and off in specific blood cells in mice to determine which healthy cells can be turned into leukaemic stem cells.
Molecular Regulation Of Replicative Lifespan; Implications In Carcinogenesis And Haematopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
The lifespan of normal cells in the body is limited by the number of times they can replicate. In contrast, cancer cells can replicate indefinitely – they are immortal. Our proposed investigations will determine how the mechanisms that control cell lifespan become dysfunctional as normal cells evolve into cancer cells. Understanding these mechanisms will enable the development of new anti-cancer drugs that will reverse cell immortality and halt the replication of cancer cells.
Identifying mitogenic signalling proteins with phosphatidyl inositol lipids. Health care of an ageing population is a national priority of the community. In order to understand the factors that control cell growth and death in cancer cells signalling proteins can be identified and studied and compared with model systems from quiescent cells. Using phospholipids attached to 'fishing lines' we can search for, identify and study the function of all the downstream signalling proteins in activated c ....Identifying mitogenic signalling proteins with phosphatidyl inositol lipids. Health care of an ageing population is a national priority of the community. In order to understand the factors that control cell growth and death in cancer cells signalling proteins can be identified and studied and compared with model systems from quiescent cells. Using phospholipids attached to 'fishing lines' we can search for, identify and study the function of all the downstream signalling proteins in activated cancer cells. This will provide the basic information for drug discovery processes to target specific molecules that inhibit and control the function of the signalling proteins implicated in the growth of cancer cells.Read moreRead less