Cho Chao-Cheng, Huang Hsun-Ho, Jiang Bo-Chen, Yang Wei-Zen, Chen Yi-Ning, Yuan Hanna S
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529, ROC.
Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan 10048, ROC.
Sci Adv. 2025 Mar 28;11(13):eadu8116. doi: 10.1126/sciadv.adu8116. Epub 2025 Mar 26.
The DNA methyltransferase 3B (DNMT3B) plays a vital role in shaping DNA methylation patterns during mammalian development. DNMT3B is intricately regulated by histone H3 modifications, yet the dynamic interplay between DNMT3B and histone modifications remains enigmatic. Here, we demonstrate that the PWWP (proline-tryptophan-tryptophan-proline) domain within DNMT3B exhibits remarkable dynamics that enhances the enzyme's methyltransferase activity upon interactions with a modified histone H3 peptide (H3K4K36). In the presence of H3K4K36, both the PWWP and ADD (ATRX-DNMT3-DNMT3L) domains transition from autoinhibitory to active conformations. In this active state, the PWWP domain most often aligns closely with the catalytic domain, allowing for simultaneous interactions with H3 and DNA to stimulate DNA methylation. The prostate cancer-associated DNMT3B R545C mutant is even more dynamic and susceptible to adopting the active conformation, resulting in aberrant DNA hypermethylation. Our study suggests the mechanism by which conformational rearrangements in DNMT3B are triggered by histone modifications, ultimately unleashing its activity in DNA methylation.
DNA甲基转移酶3B（DNMT3B）在哺乳动物发育过程中塑造DNA甲基化模式方面发挥着至关重要的作用。DNMT3B受到组蛋白H3修饰的复杂调控，然而DNMT3B与组蛋白修饰之间的动态相互作用仍不清楚。在这里，我们证明DNMT3B内的PWWP（脯氨酸-色氨酸-色氨酸-脯氨酸）结构域表现出显著的动态变化，在与修饰的组蛋白H3肽（H3K4K36）相互作用时增强了该酶的甲基转移酶活性。在H3K4K36存在的情况下，PWWP和ADD（ATRX-DNMT3-DNMT3L）结构域都从自抑制构象转变为活性构象。在这种活性状态下，PWWP结构域最常与催化结构域紧密对齐，允许与H3和DNA同时相互作用以刺激DNA甲基化。前列腺癌相关的DNMT3B R545C突变体更具动态性，更容易采用活性构象，导致异常的DNA高甲基化。我们的研究揭示了组蛋白修饰触发DNMT3B构象重排的机制，最终释放其在DNA甲基化中的活性。
