{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:22:15Z","timestamp":1787678535164,"version":"build-2784847793"},"reference-count":75,"publisher":"National Academy of Sciences","issue":"35","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM119721"],"award-info":[{"award-number":["R35GM119721"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:p>\n                    DNA methyltransferase DNMT3A-mediated de novo DNA methylation is important for proper regulation of gene expression and genomic stability in development. The DNMT3A R882H (DNMT3A\n                    <jats:sup>R882H<\/jats:sup>\n                    ) mutation, a hot-spot mutation in acute myeloid leukemia and developmental disorders, exerts a dominant-negative effect in DNMT3A-mediated DNA methylation through promoting high-order protein assembly. However, due to the lack of structural knowledge on DNMT3A homo-oligomers, the mechanism behind wild-type DNMT3A (DNMT3A\n                    <jats:sup>WT<\/jats:sup>\n                    ) and DNMT3A\n                    <jats:sup>R882H<\/jats:sup>\n                    polymerization remains unclear. Here, we report the single-particle cryo-EM structures of homo-oligomeric DNMT3A\n                    <jats:sup>WT<\/jats:sup>\n                    and filamentous DNMT3A\n                    <jats:sup>R882H<\/jats:sup>\n                    , revealing the role of the regulatory Pro-Trp-Trp-Pro (PWWP) and ATRX-DNMT3-DNMT3L (ADD) domains of DNMT3A in their dynamic assembly. While the oligomeric assembly of DNMT3A is mainly driven by the well-characterized oligomer interfaces in the methyltransferase domain, the autoinhibitory interaction of the PWWP and ADD domains in DNMT3A places them in a position for intermolecular contact, thereby contributing to the filamentous assembly of DNMT3A\n                    <jats:sup>R882H<\/jats:sup>\n                    . Disrupting the autoinhibitory interaction facilitates the transition of DNMT3A\n                    <jats:sup>R882H<\/jats:sup>\n                    polymer toward the low-order oligomeric assembly, reinforcing the aggregation-attenuation effect of the previously characterized oligomer-interface mutation R676K. Together, this study uncovers a multidomain cooperated assembly mechanism for DNMT3A, with important implication in development of effective therapeutic strategies against DNMT3A\n                    <jats:sup>R882H<\/jats:sup>\n                    -associated diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2609226123","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:36:09Z","timestamp":1787675769000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Multidomain interaction governs the filamentous assembly of the dominant-negative DNMT3A R882H mutant"],"prefix":"10.1073","volume":"123","author":[{"given":"Jianbin","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03nawhv43","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, University of 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