MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes

Samah Al-Harthi, Hao Li, Alyssa Winkler, Kacper Szczepski, Jing Deng, Jolanta Grembecka, Tomasz Cierpicki, Lukasz Jaremko

Research output: Contribution to journalArticlepeer-review


ASH1L is a histone methyltransferase that regulates gene expression through methylation of histone H3 on lysine K36. While the catalytic SET domain of ASH1L has low intrinsic activity, several studies found that it can be vastly enhanced by the interaction with MRG15 protein and proposed allosteric mechanism of releasing its autoinhibited conformation. Here, we found that full-length MRG15, but not the MRG domain alone, can enhance the activity of the ASH1L SET domain. In addition, we showed that catalytic activity of MRG15-ASH1L depends on nucleosome binding mediated by MRG15 chromodomain. We found that in solution MRG15 binds to ASH1L, but has no impact on the conformation of the SET domain autoinhibitory loop or the S-adenosylmethionine cofactor binding site. Moreover, MRG15 binding did not impair the potency of small molecule inhibitors of ASH1L. These findings suggest that MRG15 functions as an adapter that enhances ASH1L catalytic activity by recruiting nucleosome substrate.
Original languageEnglish (US)
JournalStructure (London, England : 1993)
StatePublished - Jul 31 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-08-04
Acknowledged KAUST grant number(s): OSR-CRG2018-3792, OSR-CRG2019-4088
Acknowledgements: This publication is based upon work supported by the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) under Award No. OSR-CRG2018-3792 and Award No. OSR-CRG2019-4088 (L.J.). This work was funded by the National Institutes of Health (NIH) R01 grants CA244254 (J.G.), CA207272 (T.C.) and T.C. is a Rogel Scholar. Construct encoding MRG domain has been obtained from Ishwar Radhakrishnan (Northwestern University). Constructs encoding human histones have been obtained from Wolfgang Fischle (KAUST). Construct encoding ASH1LSET-C has been obtained from Masoud Vedadi (University of Toronto).

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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