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Updated: Apr 9, 2026

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
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Published on: September 20, 2016

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Probing the Cancer Mutational Landscape of KMT2 Regulatory Subunits

Sabrina Grégoire1,2, Sara Chow1,2, Monika Joshi1,2

  • 1Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 8, 2026
PubMed

Insights

Cancer mutations in KMT2 regulatory subunits like WDR5, RbBP5, ASH2L, and DPY-30 were characterized. Some mutations revealed gain-of-function effects in ASH2L, offering new therapeutic targets for cancer.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • Lysine MethylTransferase 2 (KMT2) family proteins are frequently altered in various cancers.
  • Mutations often affect key functional regions of KMT2 regulatory subunits, including WDR5, RbBP5, ASH2L, and DPY-30.

Purpose of the Study:

  • To systematically characterize cancer-associated mutations impacting the WDR5/RbBP5/ASH2L/DPY-30 (WRAD) complex formation.
  • To investigate the functional consequences of these mutations on protein interactions and complex stability.

Main Methods:

  • Binding assays to assess protein-protein interactions.
  • Thermal stability assays to evaluate complex integrity.
  • Systematic mutational analysis of key residues within the WRAD complex.

Main Results:

  • Several cancer mutations did not disrupt ASH2L binding to DPY-30 or RbBP5.
  • Identified gain-of-function ASH2L mutants influencing RbBP5 binding through long-range interactions.
  • Discovered RbBP5 mutations weakening WDR5 interactions and defined the optimal WDR5-binding motif.

Conclusions:

  • Cancer-associated mutations can lead to gain-of-function in ASH2L, impacting epigenetic regulation.
  • Understanding these mutations provides a basis for developing novel therapeutic strategies targeting the WRAD complex.
  • Defined the WDR5-binding motif of RbBP5, aiding in the design of targeted therapies.
Keywords:
cancerhistone‐lysine N‐methyltransferasemutationprotein stabilityprotein–protein interaction network

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