{"doi":"10.1101/2021.12.28.474374","title":"Structure of telomerase-bound CST with Polymerase α-Primase","abstract":"Telomeres are the physical ends of linear chromosomes, composed of short repeating sequences (e.g. TTGGGG in Tetrahymena for the G-strand) of double-stranded DNA with a single-strand 3’-overhang of the G-strand and a group of proteins called shelterin 1,2 . Among these, TPP1 and POT1 associate with the 3’-overhang, with POT1 binding the G-strand 3 and TPP1 recruiting telomerase via interaction with telomerase reverse transcriptase (TERT) 4 . The ends of the telomeric DNA are replicated and maintained by telomerase 5 , for the G-strand, and subsequently DNA Polymerase α-Primase 6,7 (PolαPrim), for the C-strand 8 . PolαPrim is stimulated by CTC1–STN1–TEN1 (CST) 9–12 , but the structural basis of both PolαPrim and CST recruitment to telomere ends remains unknown. Here we report cryo-EM structures of Tetrahymena CST in the context of telomerase holoenzyme, both in the absence and presence of PolαPrim, as well as of PolαPrim alone. Ctc1 binds telomerase subunit p50, a TPP1 ortholog, on a flexible Ctc1 binding motif unveiled jointly by cryo-EM and NMR spectroscopy. PolαPrim subunits are arranged in a catalytically competent conformation, in contrast to previously reported autoinhibited conformation. Polymerase POLA1 binds Ctc1 and Stn1, and its interface with Ctc1 forms an entry port for G-strand DNA to the POLA1 active site. Together, we obtained a snapshot of four key players required for telomeric DNA synthesis in a single complex—telomerase core RNP, p50/TPP1, CST and PolαPrim—that provides unprecedented insights into CST and PolαPrim recruitment and handoff between G-strand and C-strand synthesis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":228107,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":501316,"name":"He Song","orcid":"0000-0001-6630-8508","position":1,"is_corresponding":false},{"id":832887,"name":"Henry Chan","orcid":"0000-0002-8198-7737","position":2,"is_corresponding":false},{"id":501315,"name":"Yaqiang Wang","orcid":"0000-0002-6822-4778","position":3,"is_corresponding":false},{"id":650011,"name":"Baocheng Liu","orcid":"0000-0001-7895-9455","position":4,"is_corresponding":false},{"id":502177,"name":"Lukas Sušac","orcid":null,"position":5,"is_corresponding":false},{"id":266761,"name":"Z. Hong Zhou","orcid":"0000-0002-8373-4717","position":6,"is_corresponding":false},{"id":379034,"name":"Juli Feigon","orcid":"0000-0003-3376-435X","position":7,"is_corresponding":false},{"id":369773,"name":"Yao He","orcid":"0000-0002-1368-6422","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-18T23:54:50.414605Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}