Evidence that ubiquitylated H2B corrals hDot1L on the nucleosomal surface to induce H3K79 methylation

Linjiao Zhou, Matthew T. Holt, Nami Ohashi, Aishan Zhao, Manuel M. Müller, Boyuan Wang, Tom W. Muir

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Ubiquitylation of histone H2B at lysine 120 (H2B-Ub), a post-translational modification first discovered in 1980, plays a critical role in diverse nuclear processes including the regulation of transcription and DNA damage repair. Herein, we use a suite of protein chemistry methods to explore how H2B-Ub stimulates hDot1L-mediated methylation of histone H3 on lysine 79 (H3K79me). By using semisynthetic 'designer' chromatin containing H2B-Ub bearing a site-specifically installed photocrosslinker, here we report an interaction between a functional hotspot on ubiquitin and the N-terminus of histone H2A. Our biochemical studies indicate that this interaction is required for stimulation of hDot1L activity and leads to a repositioning of hDot1L on the nucleosomal surface, which likely places the active site of the enzyme proximal to H3K79. Collectively, our data converge on a possible mechanism for hDot1L stimulation in which H2B-Ub physically 'corrals' the enzyme into a productive binding orientation.

Original languageEnglish (US)
Article number10589
JournalNature communications
StatePublished - Feb 2 2016

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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