Structural mechanisms of telomere maintenance: Visualizing human telomeric complexes by cryo-EM

The telomerase and shelterin complexes play a central role in maintaining telomeres, the repetitive nucleoprotein structures that cap chromosome ends. Telomerase reverse transcribes from an internal RNA template to restore the telomeric DNA repeats lost during replication. Shelterin, on the other hand, protects telomeres from being recognized as DNA breaks, preventing an inappropriate DNA damage response. Defects in either of these complexes compromise telomere maintenance, resulting in telomere dysfunction. This dysfunction causes genome instability and potentially cell death, and is linked to a spectrum of genetic disorders and cancers. Telomerase and shelterin have posed major challenges to their structural studies, thus limiting our molecular understanding of how they function. We used cryo-EM to determine structures of key human telomerase and shelterin complexes. Here I will discuss the mechanistic insights we have gained into telomerase activity, composition, and regulation by shelterin components. I will also share our recent progress on structural studies of shelterin complexes, which uncover how shelterin recognizes and restructures nucleosomes to cohabit telomeric chromatin.