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.
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
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.