Abstract
The ASH2L-DPY30 interaction is a structurally conserved and functionally essential component of the COMPASS family of histone methyltransferases responsible for H3K4 trimethylation. This minimalist helix-groove interface plays a critical allosteric role in stabilizing ASH2L, aligning the catalytic SET domain on nucleosomes, and enabling efficient methylation of chromatin targets. Recent structural, biochemical, and genetic studies have demonstrated that disrupting this contact-whether by point mutation, domain deletion, or competitive peptides-leads to widespread collapse of H3K4me3, transcriptional silencing of oncogenic programs, and suppression of cell proliferation, particularly in MLL-rearranged and MYC-driven cancers. In parallel, chemical-biology tools and fragment-based screening efforts have begun to yield the first ligandable scaffolds, setting the stage for drug discovery targeting this axis. This review synthesizes the current knowledge surrounding the ASH2L-DPY30 interface, covering its molecular architecture, catalytic importance, disease relevance, and therapeutic tractability. We also discuss resistance mechanisms, assay platforms, and the challenges and opportunities for translating this target into a first-in-class epigenetic therapy.