{"doi":"10.3389/fchem.2024.1330378","title":"Structural effects of inosine substitution in telomeric DNA quadruplex","abstract":"The telomeric DNA, a distal region of eukaryotic chromosome containing guanine-rich repetitive sequence of (TTAGGG)n, has been shown to adopt higher-order structures, specifically G-quadruplexes (G4s). Previous studies have demonstrated the implication of G4 in tumor inhibition through chromosome maintenance and manipulation of oncogene expression featuring their G-rich promoter regions. Besides higher order structures, several regulatory roles are attributed to DNA epigenetic markers. In this work, we investigated how the structural dynamics of a G-quadruplex, formed by the telomeric sequence, is affected by inosine, a prevalent modified nucleotide. We used the standard (TTAGGG) n telomere repeats with guanosine mutated to inosine at each G position. Sequences (GGG) 4 , (IGG) 4 , (GIG) 4 , (GGI) 4 , (IGI) 4 , (IIG) 4 , (GII) 4, and (III) 4 , bridged by TTA linker, are studied using biophysical experiments and molecular modeling. The effects of metal cations in quadruplex folding were explored in both Na + and K + containing buffers using CD and UV-melting studies. Our results show that antiparallel quadruplex topology forms with the native sequence (GGG) 4 and the terminal modified DNAs (IGG) 4 and (GGI) 4 in both Na + and K + containing buffers. Specifically, quadruplex hybrid was observed for (GGG) 4 in K + buffer. Among the other modified sequences, (GIG) 4 , (IGI) 4 and (GII) 4 show parallel features, while (IIG) 4 and (III) 4 show no detectable conformation in the presence of either Na + or K + . Our studies indicate that terminal lesions (IGG) 4 and (GGI) 4 may induce certain unknown conformations. The folding dynamics become undetectable in the presence of more than one inosine substitution except (IGI) 4 in both buffer ions. In addition, both UV melting and CD melting studies implied that in most cases the K + cation confers more thermodynamic stability compared to Na + . Collectively, our conformational studies revealed the diverse structural polymorphisms of G4 with position dependent G-to-I mutations in different ion conditions.","journal":"Frontiers in Chemistry","year":2024,"id":475310,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1312406,"name":"Ricky Dartawan","orcid":null,"position":1,"is_corresponding":false},{"id":1312091,"name":"Yuhan Wu","orcid":"0000-0002-0345-6324","position":2,"is_corresponding":false},{"id":1312407,"name":"Chengze Wu","orcid":null,"position":3,"is_corresponding":false},{"id":1312408,"name":"Hope Zhang","orcid":null,"position":4,"is_corresponding":false},{"id":1312409,"name":"Jeanne Lu","orcid":null,"position":5,"is_corresponding":false},{"id":1272184,"name":"Ashley Hu","orcid":"0000-0003-0310-2742","position":6,"is_corresponding":false},{"id":404740,"name":"Sweta Vangaveti","orcid":"0000-0002-2274-9544","position":7,"is_corresponding":false},{"id":250413,"name":"Jia Sheng","orcid":"0000-0001-6198-390X","position":8,"is_corresponding":false},{"id":252912,"name":"Ya Ying Zheng","orcid":null,"position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:06:16.992586Z","pmid":"38312345","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":[]}