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Abstract Isoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of this process may cause aberrant DNA methylation and pathogenesis. However, the molecular basis underlying DNMT3A1−nucleosome interaction remains elusive. Here we report the cryo-EM structure of DNMT3A1’s ubiquitin-dependent recruitment (UDR) fragment complexed with H2AK119ub1-modified nucleosome. DNMT3A1 UDR occupies an extensive nucleosome surface, involving the H2A-H2B acidic patch, a surface groove formed by H2A and H3, nucleosomal DNA, and H2AK119ub1. The DNMT3A1 UDR’s interaction with H2AK119ub1 affects the functionality of DNMT3A1 in cells in a context-dependent manner. Our structural and biochemical analysis also reveals competition between DNMT3A1 and JARID2, a cofactor of polycomb repression complex 2 (PRC2), for nucleosome binding, suggesting the interplay between different epigenetic pathways. Together, this study reports a molecular basis for H2AK119ub1-dependent DNMT3A1−nucleosome association, with important implications in DNMT3A1-mediated DNA methylation in development.

Abstract DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

In mammals, de novo DNA methyltransferase DNMT3B is essential for establishing DNA methylation patterns during embryonic development. Here the authors provide a structure-function characterization of homo-oligomeric DNMT3B, revealing the molecular basis for its vulnerability to ICF mutations.

m6Am is a modification of the 5′ end of mRNAs catalyzed by PCIF1. Here, Zhang et al. show that HIV infection induces a decrease in m6Am of cellular mRNAs through Vpr-mediated PCIF1 ubiquitination and degradation, resulting in increased HIV replication through regulation of host transcription factors.

How histone modifications crosstalk with DNA methylation to regulate epigenomic patterning and genome stability in mammals remains elusive. Here, the authors show that DNA methyltransferase DNMT1 is a reader for histone H4K20 trimethylation via its BAH1 domain, which leads to optimal maintenance of DNA methylation at repetitive LINE-1 elements.

In mammals, DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B. Here the authors report the crystal structures of DNMT3B in complex with both CpG and CpA DNA, providing insight into the substrate-recognition mechanism underpinning the divergent genomic methylation activities of DNMT3A and DNMT3B.

Cells respond to heat shock with transcriptional and translational adaptations but how HSP90 inhibition alters the heat shock proteome is largely unclear. Here, the authors analyze proteome changes upon HSP90 inhibition and show that an m6A-mediated mechanism contributes to the heat shock-induced upregulation of DNAJB4.

AGO2 is a core component of the RNAi machinery and contributes to plant immunity during bacterial infection. Here the authors show that AGO2 activity is suppressed by arginine methylation which not only promotes AGO2 degradation but also recruits TSN proteins to degrade AGO2-associated small RNAs.

Greening disease threatens the productivity of citrus crops worldwide yet the pathosystem is poorly understood. Here, Clark et al. show that an effector cloned from the associated bacteria can suppress host plant papain-like cysteine proteases' activity, suggesting its probable role in pathogenesis.