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| Title | Structure of Tetrahymena telomerase-bound CST with polymerase α-primase. |
|---|---|
| Journal, issue, pages | Nature, Vol. 608, Issue 7924, Page 813-818, Year 2022 |
| Publish date | Jul 13, 2022 |
 Authors | Yao He / He Song / Henry Chan / Baocheng Liu / Yaqiang Wang / Lukas Sušac / Z Hong Zhou / Juli Feigon /  |
| PubMed 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- ...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 TIN2. TPP1 and POT1 associate with the 3' overhang, with POT1 binding the G-strand and TPP1 (in complex with TIN2) recruiting telomerase via interaction with telomerase reverse transcriptase (TERT). The telomere DNA ends are replicated and maintained by telomerase, for the G-strand, and subsequently DNA polymerase α-primase (PolαPrim), for the C-strand. PolαPrim activity is stimulated by the heterotrimeric complex CTC1-STN1-TEN1 (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. |
 External links | Nature / PubMed:35831498 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.9 - 4.5 Å |
| Structure data | EMDB-26863, PDB-7uy5:  EMDB-26864: Tetrahymena telomerase with CST-PolaPrim EMDB-26865, PDB-7uy6: EMDB-26866, PDB-7uy7: EMDB-26867, PDB-7uy8:  EMDB-26868: Tetrahymena Polymerase alpha-Primase subunits POLA2-POLA1-PRIM2  EMDB-26869: Tetrahymena Polymerase alpha-Primase subunits PRIM2-PRIM1 |
| Chemicals |  ChemComp-ZN: |
| Source |
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 Keywords |  REPLICATION / telomerase / RNP / CST / reverse transcriptase / polymerase / primase |
