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 telomerase variants confer cancer risk, and how sequence content contributes to telomere structure and function. 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.
Characterisation of the TERT locus
TERT is one of two coding genes in a locus at 5p15 which is associated with risk of many cancer types. TERT encodes the telomerase reverse transcriptase component, which provides the catalytic activity of telomerase. Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) within the TERT locus that are associated with risk of serous epithelial ovarian cancer and breast cancer. Experimental data indicate that cancer risk is conferred by decreased telomerase activity, which results in elevated genomic instability. We are investigating the functional consequences of cancer-associated SNPs and the mechanisms by which telomerase becomes activated during cellular immortalisation.
Telomere sequence content
Telomeres are thought to comprise almost exclusively hexameric TTAGGG repeats. We have used whole genome sequencing to demonstrate that telomeres also contain substantial amounts of variant repeats that are generated in cells using either telomerase or alternative lengthening of telomeres (ALT). Variant repeats display different protein binding capabilities compared to the canonical repeat sequence. We are investigating variant repeat content, the mechanisms of variant repeat generation, and how variant repeats impact upon telomeric protein binding and telomere function.