Telomeres are nucleoprotein structures at the ends of linear chromosomes that contribute to the maintenance of chromosome integrity. Telomere length regulation involves an intricate balance between lengthening and shortening processes, which ultimately determines the proliferative capacity of a cell. Telomere length dysregulation can result in cancer, or in an emerging spectrum of premature ageing disorders. The Pickett lab is investigating the mechanism of telomere rapid deletion by telomere trimming, how telomere length contributes to cell proliferation and human health, and how telomere maintenance mechanisms become activated in cancer cells. The Pickett lab is also using next generation sequencing technologies to study telomere length and telomere sequence content. This research will underpin further clinical studies, and will impact upon cancer control and the treatment of short telomere syndromes.
Telomere rapid deletion by telomere trimming involves homologous recombination-mediated resolution of the terminal t-loop, and functions to prevent the persistence of over-lengthened telomeres. Telomere trimming does not elicit a DNA damage response, indicating that the mechanism is a normal well-regulated cellular process. We have identified telomere trimming in normal human cells of germline and somatic origin and in mouse somatic tissues, and are currently investigating telomere trimming in other proliferating cells. In addition, we are characterising the functional proteins and cell signalling responses that regulate telomere trimming.
Telomere Maintenance Mechanisms
Short telomeres are associated with adverse health outcomes, including increased risk of multiple diseases such as cardiovascular disease and cancer. Telomeres can be extended by two known mechanisms: the enzyme telomerase, which uses an intrinsic RNA template sequence to reverse transcribe telomeric repeats onto the chromosome end, and the Alternative Lengthening of Telomeres (ALT) pathway, a recombination-dependent replication mechanism that utilises a variety of DNA repair pathways to extend chromosome ends. Telomerase is active in the human germline, early in embryogenesis and in some stem and progenitor cell populations to enable increased proliferative capacity. Cancer cells activate either telomerase or ALT to repair eroded or dysfunctional telomeres to ensure proliferative immortality. The Pickett lab is investigating telomerase activation, as well as the processes that regulate telomerase biogenesis and recruitment. The Pickett lab also works extensively on characterising the mechanism of ALT-mediated telomere lengthening in cancer cells.
Telomere Sequence Content
Telomeres are thought to comprise almost exclusively hexameric TTAGGG repeats. The Pickett lab have been using whole genome sequencing to demonstrate that telomeres also contain abundant variant telomeric repeats, which contribute to telomere biology. We are currently employing next generation sequencing techniques to accurately measure telomere sequence content, and using this information to characterise telomere length and telomere maintenance mechanisms in large-scale whole genome sequencing datasets.