UC Irvine

In most eukaryotes, telomeres are the natural chromosome ends that are essentially involved in stable maintenance of chromosomes by facilitating chromosomes end replication and preventing them from degradation or end fusion. Hyper-activated telomere-extension activity, including both upregulation of positive regulators and downregulation of the negative regulators, potentially leads to uncontrolled proliferation that is required in cancer cells; inversely, degenerative disorders and premature aging are often accompanied with impaired or lost telomere extension. Similar to human, in fission yeast Schizosaccharomyces pombe, telomere structure is achieved by association of shelterin with both double-stranded and single-stranded telomeric DNA forming a nucleoprotein complex. Despite vital roles of shelterin components and telomere structure in telomere length regulation, structural characterizations of assembly and disassembly of shelterin are still limited, which in turn impedes our understanding of the mechanism in which the telomere length homeostasis is maintained.

To this end, we solved the crystal structure of the core part of fission yeast shelterin that reveals essential atomic-level information for cooperative assembly of shelterin bridge. Intriguingly, this cooperativity is also utilized in the human shelterin counterparts, suggesting a highly conserved driving force for shelterin formation. Moreover, this hierarchical formation not only exists within shelterin components, but also occurs in telomerase recruitment to telomere via a bivalent binding event between shelterin and telomerase.