{"doi":"10.1073/pnas.2024889118","title":"The structurally conserved TELR region on shelterin protein TPP1 is essential for telomerase processivity but not recruitment","abstract":"<jats:title>Significance</jats:title>\n                  <jats:p>Telomerase directs the synthesis of new telomeric repeats at chromosome ends, enabling cells to overcome the end replication problem and to continue to divide. The shelterin protein TPP1 interacts with telomerase, promoting both telomerase recruitment and processivity (the addition of multiple telomeric repeats after a single substrate binding event). Here, we identify separation-of-function mutants of TPP1 that eliminate telomerase processivity but leave the telomerase recruitment function intact. When introduced into human cells in a homozygous manner, these mutations can induce critical telomere shortening and cellular senescence. Our observations therefore demonstrate that TPP1 stimulation of telomerase processivity is a key regulatory step in vivo for telomerase-mediated extension of telomeres and continued cell proliferation.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":508700,"datarank":0.4320855168528932,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.08669775290378626,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.08669775290378626,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":8,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":1,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":414522,"name":"Madhav Sharma","orcid":"0000-0003-0068-5508","position":1,"is_corresponding":false},{"id":1360724,"name":"Derek Wei","orcid":null,"position":2,"is_corresponding":false},{"id":1360725,"name":"Lifeng Xu","orcid":"0000-0002-7887-5451","position":3,"is_corresponding":false},{"id":509858,"name":"Ranjodh Sandhu","orcid":"0009-0008-2340-3423","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The structurally conserved TELR region on shelterin protein TPP1 is essential for telomerase processivity but not recruitment","abstract":"<jats:title>Significance</jats:title>\n                  <jats:p>Telomerase directs the synthesis of new telomeric repeats at chromosome ends, enabling cells to overcome the end replication problem and to continue to divide. The shelterin protein TPP1 interacts with telomerase, promoting both telomerase recruitment and processivity (the addition of multiple telomeric repeats after a single substrate binding event). Here, we identify separation-of-function mutants of TPP1 that eliminate telomerase processivity but leave the telomerase recruitment function intact. When introduced into human cells in a homozygous manner, these mutations can induce critical telomere shortening and cellular senescence. Our observations therefore demonstrate that TPP1 stimulation of telomerase processivity is a key regulatory step in vivo for telomerase-mediated extension of telomeres and continued cell proliferation.</jats:p>","is_dataset_classified":null,"base_score":2.302585092994046,"endowment":2.302585092994046,"datacite_reuse_total":1,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34282008","pmcid":"PMC8325329","openalex_id":"https://openalex.org/W3185209785","authors":[],"funders":[{"funder_name":"American Cancer Society","grant_id":"RSG-12-069-01-DMC","title":null}],"total_grants":1,"fwci":0.5973,"citation_percentile":0.65991958,"influential_citations":0,"citation_trend":[{"year":2022,"count":1},{"year":2023,"count":3},{"year":2024,"count":1},{"year":2025,"count":1},{"year":2026,"count":3}],"oa_status":"green","license":"https://www.pnas.org/site/aboutpnas/licenses.xhtml","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8325329","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8325329","host_type":"repository"},{"url":"http://www.pnas.org/syndication/doi/10.1073/pnas.2024889118","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.2024889118","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.2024889118","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34282008","host_type":"repository"},{"url":"https://escholarship.org/uc/item/3vs2g8nt","host_type":"repository"}],"fields_of_study":["Telomeres, Telomerase, and Senescence","RNA Interference and Gene Delivery","CRISPR and Genetic Engineering","Humans","Mutation","Shelterin Complex","Telomerase","Telomere Homeostasis","Telomere-Binding Proteins","Telomeric Repeat Binding Protein 2"],"mesh_terms":["Shelterin Complex","Humans","Mutation","Telomerase","Telomere-Binding Proteins","Telomeric Repeat Binding Protein 2","Telomere Homeostasis"],"keywords":["Telomerase","Processivity","Telomere","Biology","Shelterin","Telomerase RNA component","Cell biology","Molecular biology","Telomerase reverse transcriptase","Genetics","DNA-binding protein","DNA","DNA replication","Transcription factor","Gene","Long-term Cell Viability","Separation-of-function","Telomerase Processivity","Shelterin Protein Tpp1","Telomere Extension"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Life in Land"}],"linked_datasets":[{"doi":"10.17920/g95b2z","title":"Identifying cellular factors that inhibit telomerase","publisher":"University of California Office of the President","resource_type":"Award"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-19T02:41:57.756577Z","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":[]}