Most of the work in the Cancer Research Unit (CRU) currently focuses on understanding telomeres
and how these structures at the ends of chromosomes are maintained in cancer cells. Telomeres shorten each time a cell divides, and this acts as a countdown eventually telling cells to stop proliferating. Cancer cells are able to counteract the shortening process and continue to proliferate out of control. In order to keep growing, the cancer cells must activate the enzyme telomerase or the Alternative Lengthening of Telomeres (ALT) mechanism, either of which can counteract telomere shortening. The ALT mechanism was originally discovered by the CRU, and the team continues to focus on understanding how this mechanism works, and most importantly, how to inhibit it in order to treat cancer.
Telomere chromatin in ALT
We are investigating many aspects of telomere chromatin structure and telomere biology, including telomere length trimming and telomeric DNA sequences. Our aim is to understand how ALT telomeres are structured and how they differ from telomeres in normal and telomerase-positive cells. This will help us to understand the ALT mechanism in more detail and provide information on possible targets for interfering with ALT activity in cancer cells.
Genes involved in ALT
The C-circle assay for detecting ALT activity, which was developed by Jeremy Henson in our laboratory, has enabled us to search for the genes that repress ALT in normal cells. We are also using this and other techniques to find the genes needed for ALT activity. These studies will enable us to find targets for the development of ALT-inhibiting therapeutic drugs to treat cancer.
ALT in normal tissues
We have developed a way to detect ALT activity in mouse tissues by demonstrating that a DNA sequence introduced into the telomere can be copied from telomere to telomere. We are developing this technology to further study how low levels of ALT activity can become sufficiently elevated to prevent telomere shortening and allow unlimited proliferation of cancer cells.