Structure of Tetrahymena telomerase-bound CST with polymerase α-primase

Yao He, He Song, Henry Chan, Baocheng Liu, Yaqiang Wang, Lukas Sušac, Z. Hong Zhou and Juli Feigon ()
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Yao He: University of California, Los Angeles
He Song: University of California, Los Angeles
Henry Chan: University of California, Los Angeles
Baocheng Liu: University of California, Los Angeles
Yaqiang Wang: University of California, Los Angeles
Lukas Sušac: University of California, Los Angeles
Z. Hong Zhou: University of California, Los Angeles
Juli Feigon: University of California, Los Angeles

Nature, 2022, vol. 608, issue 7924, 813-818

Abstract: Abstract Telomeres are the physical ends of linear chromosomes. They are composed of short repeating sequences (such as TTGGGG in the G-strand for Tetrahymena thermophila) of double-stranded DNA with a single-strand 3′ overhang of the G-strand and, in humans, the six shelterin proteins: TPP1, POT1, TRF1, TRF2, RAP1 and TIN21,2. TPP1 and POT1 associate with the 3′ overhang, with POT1 binding the G-strand3 and TPP1 (in complex with TIN24) recruiting telomerase via interaction with telomerase reverse transcriptase5 (TERT). The telomere DNA ends are replicated and maintained by telomerase6, for the G-strand, and subsequently DNA polymerase α–primase7,8 (PolαPrim), for the C-strand9. PolαPrim activity is stimulated by the heterotrimeric complex CTC1–STN1–TEN110–12 (CST), but the structural basis of the recruitment of PolαPrim and CST to telomere ends remains unknown. Here we report cryo-electron microscopy (cryo-EM) structures of Tetrahymena CST in the context of the telomerase holoenzyme, in both the absence and the presence of PolαPrim, and of PolαPrim alone. Tetrahymena Ctc1 binds telomerase subunit p50, a TPP1 orthologue, on a flexible Ctc1 binding motif revealed by cryo-EM and NMR spectroscopy. The PolαPrim polymerase subunit POLA1 binds Ctc1 and Stn1, and its interface with Ctc1 forms an entry port for G-strand DNA to the POLA1 active site. We thus provide a snapshot of four key components that are required for telomeric DNA synthesis in a single active complex—telomerase-core ribonucleoprotein, p50, CST and PolαPrim—that provides insights into the recruitment of CST and PolαPrim and the handoff between G-strand and C-strand synthesis.

Date: 2022
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DOI: 10.1038/s41586-022-04931-7

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