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
Manipulating The B-RAF/MEK Pathway In The Genesis And Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The use of small molecule inhibitors is the most promising strategy for treating melanoma. In this project, we will examine the mechanisms of resistance to this class of drugs and define new drug targets by examining the molecular-circuitry that is damaged in melanomas. This work will greatly accelerate the development of new th ....Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The use of small molecule inhibitors is the most promising strategy for treating melanoma. In this project, we will examine the mechanisms of resistance to this class of drugs and define new drug targets by examining the molecular-circuitry that is damaged in melanomas. This work will greatly accelerate the development of new therapies.Read moreRead less
Regulation Of Amyloid-beta Production By Glycosphingolipid Synthesis Inhibition
Funder
National Health and Medical Research Council
Funding Amount
$549,925.00
Summary
Alzheimer's disease (AD) prevalence is rising and there is currently no curative treatment. Production of neurotoxic amyloid-beta peptide (Abeta) in the brain is thought to be one causative factor in AD. We have recently discovered a new drug that alters lipid levels in cell membranes and potently inhibits Abeta production by neurons. We will define precisely how this drug works and examine its potential to reduce Abeta accumulation in the brains of mice genetically engineered to mimic AD.
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
Definition Of The Role Of Senescence In Tumour-associated Endothelial Cells.
Funder
National Health and Medical Research Council
Funding Amount
$583,081.00
Summary
'Cellular senescence' is a mechanism to stop cells growing, and it may protect against tumour growth. However, it may also induce changes in cells leading to 'pro-tumour' effects. We have identified a gene - which we have called SEN1 - which induces senescence in the blood vessels of tumours. This gene may cause alterations in the blood supply to the tumour allowing it to grow and to resist chemotherapy. Understanding this gene may allow us to treat cancer by shutting off its blood supply.