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A minimalist helix–groove interface stabilizes ASH2L, positions the catalytic SET domain on nucleosomes, and supports efficient chromatin methylation. Structural, biochemical, and genetic studies show that disrupting the contact collapses H3K4me3 and silences oncogenic transcription, suppressing proliferation in MLL-rearranged and MYC-driven cancers. Chemical-biology tools and fragment-based screening are beginning to identify ligandable scaffolds, enabling drug discovery and review of resistance mechanisms, assay platforms, and translational challenges.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/disrupting-the-ash2ldpy30-ppi-in-cancer-structure-function-and-therapeutic-opportunities-in-h3k4-methylation/348996/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/disrupting-the-ash2ldpy30-ppi-in-cancer-structure-function-and-therapeutic-opportunities-in-h3k4-methylation/348996.png","ImageObject",300,407,{"name":92,"@type":93},"Alex Sinclair","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the role of the ASH2L–DPY30 interaction in H3K4 trimethylation?","Question",{"text":112,"@type":113},"It forms a conserved helix–groove interface that stabilizes ASH2L, aligns the SET catalytic domain on nucleosomes, and enables efficient H3K4 trimethylation.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does disrupting ASH2L–DPY30 affect cancer cells?",{"text":117,"@type":113},"Disruption (e.g., point mutation, domain deletion, or competitive peptides) collapses H3K4me3, silences oncogenic transcriptional programs, and suppresses cell proliferation, especially in MLL-rearranged and MYC-driven cancers.",{"name":119,"@type":110,"acceptedAnswer":120},"What therapeutic strategies are discussed for targeting the ASH2L–DPY30 axis?",{"text":121,"@type":113},"The review highlights chemical-biology approaches and fragment-based screening that aim to discover ligandable scaffolds, along with discussion of resistance mechanisms, assay platforms, and challenges for translating this target into an epigenetic therapy.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},348996,1790277208,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099523882182,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Kamel et al. Epigenetics & Chromatin (2026) 19:16 [https://doi.org/10.1186/s13072-026-00663-4](https://doi.org/10.1186/s13072-026-00663-4)  \nEpigenetics & Chromatin  \nREVIEW Open Access  \nDisrupting the ASH2L–DPY30 PPI in cancer: structure, function, and therapeutic opportunities in H3K4 methylation  \nEmadeldin M. Kamel 1*, Ahmed A. Allam2, Hassan A. Rudayni2, Saleh Alkhedhairi3, Noha A. Ahmed4, Faris F. Aba Alkhayl5 and Al Mokhtar Lamsabhi6  \nAbstract  \nThe 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.  \nKeywords ASH2L, DPY30, H3K4 trimethylation, Protein–protein interaction, Epigenetic therapy  \n*Correspondence: Emadeldin M. Kamel  \n[emad.abdelhameed@science.bsu.edu.eg](emad.abdelhameed@science.bsu.edu.eg)  \n1Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt  \n2Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia  \n3Department of Medical Biosciences, College of Veterinary Medicine, Qassim University, P. O. Box 6622, Buraidah 51452, Saudi Arabia 4Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P. O. Box 62521, Beni-Suef, Egypt  \n5Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia 6Departamento de Química and Institute for advanced research in chemical Science (IAdChem), Facultad de Ciencias, Universidad Autónoma de Madrid, Módulo 13, 28049 Madrid, Spain  \nIntroduction  \nHistone H3 lysine-4 (H3K4) methylation is a hallmark of active or poised chromatin and a key gate-keeper of transcriptional plasticity [1]. Because many tumors rewire the H3K4 methyl-landscape, the writers, erasers and readers of this mark have become attractive drug targets in “epigenetic oncology” [1]. In mammals, H3K4 mono-, di- and trimethylation is catalyzed by six COMPASS/ SET1 family holo-enzymes (SET1A/B, MLL1-4) [2–4]. Each complex is built around a catalytic SET protein and four obligate core subunits—WDR5, RBBP5, ASH2Land DPY30—that act together as an allosteric engine to achieve processive trimethylation [6]. Mechanistically, H3K4me3 is established in a transcription-coupled, stepwise manner in which COMPASS complexes are  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this artic","cbCaiqYHgISBniz3","https://ap.wps.com/l/cbCaiqYHgISBniz3","pdf",4898808,26,"English","# Introduction\n## Epigenetic role of H3K4 methylation and COMPASS/SET1 enzymes\n## Architecture and catalytic importance of the ASH2L–DPY30 interface\n## Consequences of disrupting ASH2L–DPY30 in cancer\n## Therapeutic opportunities and translational challenges","[{\"question\":\"What is the role of the ASH2L–DPY30 interaction in H3K4 trimethylation?\",\"answer\":\"It forms a conserved helix–groove interface that stabilizes ASH2L, aligns the SET catalytic domain on nucleosomes, and enables efficient H3K4 trimethylation.\"},{\"question\":\"How does disrupting ASH2L–DPY30 affect cancer cells?\",\"answer\":\"Disruption (e.g., point mutation, domain deletion, or competitive peptides) collapses H3K4me3, silences oncogenic transcriptional programs, and suppresses cell proliferation, especially in MLL-rearranged and MYC-driven cancers.\"},{\"question\":\"What therapeutic strategies are discussed for targeting the ASH2L–DPY30 axis?\",\"answer\":\"The review highlights chemical-biology approaches and fragment-based screening that aim to discover ligandable scaffolds, along with discussion of resistance mechanisms, assay platforms, and challenges for translating this target into an epigenetic therapy.\"}]","Disrupting the ASH2L–DPY30 PPI in cancer - structure, function, and therapeutic opportunities in H3K4 methylation | PDF",1790081088,66]