Telomere Biology Laboratory

Previous and current research
Our research focuses on the composition and functions of telomeres, the DNA-protein complexes that form the ends of linear chromosomes. Telomeres maintain the stability of genomic DNA by preventing degradation and fusion of chromosome ends, and by ensuring that bona fide chromosome ends do not elicit the cell cycle arrest pathways that respond to damage-induced DNA breaks.Telomeres have become a particular focus of research on tumorigenesis (which is associated with genomic instability and telomerase activation) and aging (which is accompanied by a gradual decline in telomere length). However, the mechanisms underlying telomere function are not yet understood, and indeed the complete functional repertoire of telomeres remains to be defined.

Many of our studies stem from our identification of a fission yeast telomere protein, Taz1, which shares homology with the human telomere proteins hTRF1 and hTRF2. Loss of Taz1 results in a dramatic increase in telomere length and aberrations in telomeric chromatin structure. Furthermore, Taz1 is necessary for the fundamental role of telomeres in preventing natural chromosome ends from being treated as damage-induced DNA breaks. Under some conditions, chromosomes in taz1^- cells become fused via their telomeres, generating lethal dicentric chromosomes. Under other conditions, Taz1 loss does not cause telomere fusion but does cause DNA breaks to accumulate throughout the genome. Loss of Taz1 can also activate both DNA damage and spindle assembly checkpoints. During the sexual cycle, taz1^- cells encounter an additional set of problems, as meiotic telomere clustering at the spindle pole bodies is disrupted in the absence of taz1, resulting in severe meiotic problems: chromosome segregation is random, and recombination is reduced in the few viable offspring of a taz1^-/- mating.

Future projects
The diversity of phenotypes found in taz1^- cells allows us to explore not only the mechanisms underlying telomere function but also the ways in which telomere functions change with cell cycle progression and changing conditions. We can also use Taz1, as well as information on the fully-sequenced fission yeast genome, to identify additional telomere proteins. Indeed, we have recently identified and begun characterisation of a protein called Est1 that is required for telomerase activity. Issues we are pursuing include: [1] the mechanisms by which Taz1 performs its many functions, [2] the cell cycle regulation of telomere function, and the role of telomere dysfunction in impeding cell cycle progression, [3] the role of telomeres in sexual differentiation and meiosis, and [4] the identities and roles of other telomere-associated proteins in fission yeast.