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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:p>\n                    The chemical modification\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    <jats:sup>6<\/jats:sup>\n                    -methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) is catalyzed by the m\n                    <jats:sup>6<\/jats:sup>\n                    A methyltransferase complex (MTC) comprising METTL3 and METTL14 in the nucleus. Structural evidence reveals that METTL3 primarily functions as the catalytic core, while METTL14 serves as an RNA-binding scaffold. However, the mechanism directing the complex assembly in vivo remains enigmatic. Here, we demonstrate that MTC is formed by a cotranslational mechanism in which nascent METTL3 interacts with METTL14 polypeptide chain exposed from the ribosome exit tunnel. The methyltransferase domains in the subunits determine the specificity of their cotranslational interaction. In contrast, WTAP, the regulatory subunit of MTC, is recruited to the complex posttranslationally. We further identify CCT4, the key subunit of cytosolic chaperonin TCP-1, as an essential facilitator of the endogenous MTC assembly process. Depletion of CCT4 results in dramatic reduction of METTL3\u2013METTL14 heterodimer formation. Remarkably, we engineer a cell-permeable peptide M14P1, which could disrupt cotranslational assembly of MTC, thereby impairing m\n                    <jats:sup>6<\/jats:sup>\n                    A deposition and significantly attenuating the proliferation of acute myeloid leukemia (AML) cells and promoting apoptosis. Collectively, our findings unravel intrinsic mechanisms governing the in vivo assembly of MTC, and provide a potential therapeutic strategy to disrupt oncogenic m\n                    <jats:sup>6<\/jats:sup>\n                    A pathways and impede AML progression.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2517258123","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T17:39:09Z","timestamp":1767375549000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Cotranslational assembly directs the biogenesis of the m\n                    <sup>6<\/sup>\n                    A methyltransferase complex"],"prefix":"10.1073","volume":"123","author":[{"given":"Xiang","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingci","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"He","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cell Biology, School of Life Science and Technology, China Pharmaceutical University","place":["Nanjing, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034142"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1209312109"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2013.11.004"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20150159"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0462-y"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-013118-111717"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-018-0179-5"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc7151"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28878-5"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.202300024"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1867"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11112"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12730"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15377"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.10.012"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2016.03.006"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0168-5"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.04.025"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1432"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature18298"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.05.041"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18434"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.3"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.064063.117"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00725-8"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00741-8"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.02.015"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.309146.117"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-018-0019-0"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23892-5"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-019-0244-z"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-023-2526-2"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2019.02.008"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00774-x"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13737"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)47060-3"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-023-01026-3"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113099"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1059"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.8b00919"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20220591"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12192-018-0949-3"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.11.016"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-024-02350-3"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4416"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0538-8"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24678"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03536-w"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09749-y"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.03.030"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2115799119"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.11.013"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.10.026"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky156"},{"key":"e_1_3_4_55_2","first-page":"1","article-title":"Arginine methylation of METTL14 promotes RNA N 6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells","volume":"12","author":"Liu X.","year":"2021","unstructured":"X. Liu , Arginine methylation of METTL14 promotes RNA N 6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells. Nat. Commun. 12, 1\u201314 (2021).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.12.001"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.038"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1515"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2021945118"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.12.009"},{"key":"e_1_3_4_61_2","unstructured":"X. Wu X. Liu Data from \u201cIdentifying interaction proteins of METTL3 and METTL14 using APEX2-based labeling and mass spectroscopy.\u201d The Integrated Proteome Resources. https:\/\/www.iprox.cn\/\/page\/project.html?id=IPX0014551000. Deposited 5 December 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2517258123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T17:39:27Z","timestamp":1767375567000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2517258123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,2]]},"references-count":61,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,6]]}},"alternative-id":["10.1073\/pnas.2517258123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2517258123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,2]]},"assertion":[{"value":"2025-07-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2517258123"}}