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
TRF2 Protein And T-loop Replication In Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$398,156.00
Summary
Telomere loss acts as a clock telling cells when to stop proliferating. Cancer cells ignore this clock and grow indefinitely by preventing the normal loss of telomeres. Little is known about one of the methods cancers use to preserve telomeres, called ALT, which is employed by some brain tumours and other cancers. We will determine if the TRF2 protein is involved in controlling ALT. This will lay the basis for future anti-cancer treatments targeted at ALT.
Therapeutic Implications Of A Molecular Link Between Survivin And Telomerase Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
A unifying feature of all types of cancer cells is that they are immortal. Our investigations will build upon our recent results that showed the gene survivin is involved in cancer cell immortalisation. We will characterise a molecular link between survivin and the enzyme telomerase, which is central to cancer cell immortality. Furthermore, we will demonstrate the therapeutic potential of turning off both survivin and telomerase as a novel approach to halting the growth of cancer cells.
Identification And Characterisation Of Human Telomerase Holoenzyme Components
Funder
National Health and Medical Research Council
Funding Amount
$325,091.00
Summary
DNA is packaged into linear structures - chromosomes - that have two ends, called telomeres. When cells proliferate, their telomeres normally shorten slightly, and this ultimately limits the number of times cells can proliferate. This limitation is thought to contribute to ageing. Some tissues normally have a high rate of cell turnover (for example in the bone marrow which is constantly producing large numbers of new blood cells), and therefore a need for very extensive cellular proliferation. I ....DNA is packaged into linear structures - chromosomes - that have two ends, called telomeres. When cells proliferate, their telomeres normally shorten slightly, and this ultimately limits the number of times cells can proliferate. This limitation is thought to contribute to ageing. Some tissues normally have a high rate of cell turnover (for example in the bone marrow which is constantly producing large numbers of new blood cells), and therefore a need for very extensive cellular proliferation. In these tissues, an enzyme called telomerase slows down (but does not completely prevent) the rate of telomere shortening by replacing some of the DNA that is lost as a result of proliferation. Telomerase is a complex enzyme with a number of subunits. In the past few years, it has started to become clear that inherited deficiencies of some of these subunits cause diseases in which cellular proliferation starts to fail at a young age. These patients typically die of bone marrow failure. In contrast to conditions where there is telomerase deficiency, the great majority of cancers have inappropriately high levels of telomerase activity which allow cancer cells to continue dividing without limit. Telomerase is therefore regarded as a very promising target for new cancer treatments. In view of the importance of telomerase to human health, it may seem very surprising that we do not yet know all of its subunits. The reason for this is that, even in telomerase-positive cancer cells, the amount of telomerase present is vanishingly small which has made it impossible so far to obtain sufficient quantities for even the most sensitive analytical techniques. We are using very large numbers of human cells grown in a bioreactor, and have devised a highly efficient method for purifying telomerase from them. We will analyse the purified telomerase by contemporary mass spectroscopy techniques, identify all of the subunits, and characterise their contribution to telomerase function.Read moreRead less
Structure, Assembly, And Inhibition Of The Human Telomerase Enzyme Complex
Funder
National Health and Medical Research Council
Funding Amount
$645,359.00
Summary
In contrast to the limited growth of normal human cells, cancer cells proliferate out of control and without limit. At least 85% of all human cancers rely on the enzyme TELOMERASE to sustain their unlimited proliferation. Telomerase is absent in most normal tissues and therefore represents a potentially effective and specific target for future cancer therapy. We aim to determine the precise 3-dimensional shape of human telomerase to provide a template for rational anti-telomerase drug design.
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.