Clynes Group: Cancer Therapeutics, DNA Damage and Repair Laboratory
A major focus of our work is exploring how ATRX prevents normal cells from elongating their telomeres via the ALT pathway and trying to understand the role of ATRX in DNA replication and repair.
Cancer occurs through the uncontrolled growth and division of cells, which eventually leads to the development of a tumour. The number of times a cell can divide is limited by the length of specialised DNA sequences found at the end of chromosomes. These specialised sequences are called telomeres, and in normal cells they shorten with every cell division. For a cell to become cancerous it has to stop its telomeres shortening, which in turn allows the cell to continue to grow and divide.
To accomplish this, cancer cells either activate an enzyme (telomerase) that adds telomeric DNA sequences to the ends of the DNA molecules, or they copy telomeric sequences from the end of one DNA molecule to another (the alternative lengthening of telomeres (ALT) pathway).
Importantly, it is predicted that ALT positive cancers are susceptible to different therapeutic treatments than other cancers. This is particularly significant because a variety of childhood cancers, including currently untreatable brain tumours, extend their telomeres via the ALT pathway. To date there are no ALT-targeted therapeutics. Targeting the ALT pathway may provide a much needed new approach to treating these cancers.
Recent research has provided important clues as to how telomere lengthening is activated in ALT cancers. We have shown that expression of a protein ATRX, which is inactivated in most ALT cancers, suppresses telomere lengthening in ALT cells, and this suppression is likely linked to the role of ATRX in DNA replication/repair. Understanding more about how ATRX works will provide important clues for the development or identification of new drugs that inhibit this pathway.
In addition our lab is interested in the identification of new drugs that could potentially be used to target ALT cancer cells. The challenge of identifying new cancer drugs can be approached in different ways. One way is understanding which gene and proteins underpin an abnormal characteristic of a cancer cell (in this case aberrant telomere lengthening or the lack of ATRX) to identify new targets for the rational design of drugs. A second ways is screening pre-existing drug libraries and testing them for their ability to limit the growth of, or preferentially kill, ALT cancer cells that lack ATRX.