{"doi":"10.1101/2023.03.16.532618","title":"Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14","abstract":"Abstract Chemical modification of RNAs is important for post-transcriptional gene regulation. The METTL3-METTL14 complex generates most N 6 -methyladenosine (m 6 A) modifications in mRNAs, and dysregulated methyltransferase expression has been linked to numerous cancers. Here we show that changes in m 6 A modification location can impact oncogenesis. A gain-of-function missense mutation found in cancer patients, METTL14 R298P , promotes malignant cell growth in culture and in transgenic mice. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif and transforms gene expression without increasing global m 6 A levels in mRNAs. The altered substrate specificity is intrinsic to METTL3-METTL14, helping us to propose a structural model for how the METTL3-METTL14 complex selects the cognate RNA sequences for modification. Together, our work highlights that sequence-specific m 6 A deposition is important for proper function of the modification and that noncanonical methylation events can impact aberrant gene expression and oncogenesis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391270,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1163590,"name":"Luiza Guimarães Tunes","orcid":"0000-0002-7177-0059","position":1,"is_corresponding":false},{"id":997988,"name":"Meng-Hsiung Hsieh","orcid":null,"position":2,"is_corresponding":false},{"id":656536,"name":"Ping Wang","orcid":"0000-0002-2710-7188","position":3,"is_corresponding":false},{"id":366406,"name":"Ashwani Kumar","orcid":"0000-0002-8806-111X","position":4,"is_corresponding":false},{"id":1163591,"name":"Brijesh B. Khadgi","orcid":"0000-0002-6206-2552","position":5,"is_corresponding":false},{"id":670256,"name":"Yen‐Yu Yang","orcid":null,"position":6,"is_corresponding":false},{"id":1163996,"name":"Katelyn A. Doxtader","orcid":null,"position":7,"is_corresponding":false},{"id":267412,"name":"Emily Herrell","orcid":"0000-0002-4620-1778","position":8,"is_corresponding":false},{"id":1163592,"name":"Oliwia Koczy","orcid":"0000-0002-3065-780X","position":9,"is_corresponding":false},{"id":308972,"name":"Rohit Setlem","orcid":"0000-0002-6783-9965","position":10,"is_corresponding":false},{"id":1079522,"name":"Xunzhi Zhang","orcid":"0000-0002-3599-1751","position":11,"is_corresponding":false},{"id":285068,"name":"Bret M. Evers","orcid":"0000-0001-5686-0315","position":12,"is_corresponding":false},{"id":110450,"name":"Yinsheng Wang","orcid":"0000-0001-5565-283X","position":13,"is_corresponding":false},{"id":240348,"name":"Chao Xing","orcid":"0000-0002-1838-0502","position":14,"is_corresponding":false},{"id":264169,"name":"Hao Zhu","orcid":"0000-0002-8417-9698","position":15,"is_corresponding":false},{"id":30048,"name":"Yunsun Nam","orcid":"0000-0002-7939-8626","position":16,"is_corresponding":false},{"id":1163589,"name":"Chi Zhang","orcid":"0000-0002-9209-4934","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:42.653719Z","pmid":"36993753","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":[]}