Telomere Biology Lab

Formidable challenges are presented by linear chromosome ends, as their resemblance to damage-induced DNA breaks makes them vulnerable to degradation and end-joining pathways that provoke cancer. Telomeres protect chromosome ends from these events. My laboratory has uncovered crucial principles underlying these classically recognized telomere functions, and has identified unanticipated additional functions. We utilize fission yeast as this model provides easy genetic manipulation, airtight controls that are difficult to achieve in mammalian systems, and telomeres similar to those of human. Replication fork obstruction through telomeres as a key challenge and trigger for telomerase We made the surprising discovery that ‘naked’ telomeric repeats impede replication fork (RF) progression, but when bound by the telomere binding protein Taz1, RFs progress smoothly through telomeres; an analogous role for the mammalian Taz1 ortholog TRF1 was later demonstrated. We find that the fission yeast RecQ helicase (ortholog of the helicase mutated in human Werner Syndrome – a premature aging disease) instigates deleterious outcomes of stalled telomeric RFs. We also find that stalled RFs generate powerful telomerase substrates. Survival without telomeres Cells can occasionally survive the absence of telomerase, eg by maintaining telomeres via recombination. We recently identified a novel mode of telomerase-minus survival we dubbed ‘HAATI’. In HAATI cells, telomere repeats are absent but tracts of ‘generic’ heterochromatin jump to each chromosome end and, along with a non-telomeric 3’-overhang, recruit Pot1, which protects HAATI chromosome linearity. HAATI resembles the chromosome end-maintenance strategy found in Drosophila melanogaster, which lacks specific telomere sequences but assembles terminal heterochromatin structures that associate with specific end-protection factors. This discovery reveals an alternative mode by which cancer cells might survive without telomerase activation. Surprising functions for telomeres during meiosis The spindles that form at mitosis and meiosis are often thought of as semi-autonomous architectural structures that control the movement of chromosomes. Our recent findings have overturned this notion by revealing that telomeres, which gather together near the centrosome in early stages of meiosis to form the highly conserved ‘bouquet structure’, control both the formation of meiotic spindles and the attachment of chromosomes, via their centromeres, to those spindles. We are using an array of strategies to define the mechanisms by which telomeres accomplish their meiotic tasks, as well as the relevance of these observations to mitosis.