9th Annual Biomarkers Congress

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation

TypeWhite Paper Summary

Numerous post-translational modifications of histones have been described in organisms ranging from yeast to humans1. Growing evidence for dynamic regulation of these modifications, position- and modification-specific protein interactions, and biochemical crosstalk between modifications has strengthened the 'histone code' hypothesis, in which histone modifications are integral to choreographing the expression of the genome1, 2. One such modification, ubiquitylation of histone H2B (uH2B) on lysine 120 (K120) in humans3, and lysine 123 in yeast4, has been correlated with enhanced methylation of lysine 79 (K79) of histone H3 (refs 5–8), by K79-specific methyltransferase Dot1 (KMT4)9, 10, 11. However, the specific function of uH2B in this crosstalk pathway is not understood. Here we demonstrate, using chemically ubiquitylated H2B, a direct stimulation of hDot1L-mediated intranucleosomal methylation of H3 K79. Two traceless orthogonal expressed protein ligation (EPL) reactions were used to ubiquitylate H2B site-specifically. This strategy, using a photolytic ligation auxiliary and a desulphurization reaction, should be generally applicable to the chemical ubiquitylation of other proteins. Reconstitution of our uH2B into chemically defined nucleosomes, followed by biochemical analysis, revealed that uH2B directly activates methylation of H3 K79 by hDot1L. This effect is mediated through the catalytic domain of hDot1L, most likely through allosteric mechanisms. Furthermore, asymmetric incorporation of uH2B into dinucleosomes showed that the enhancement of methylation was limited to nucleosomes bearing uH2B. This work demonstrates a direct biochemical crosstalk between two modifications on separate histone proteins within a nucleosome

Keywords
Authors
Name:Victor Nizet
Name:David Bartel
Name:Katerina Akassoglou
Name:C Chatterjee
Name:R Sachidanandam
Name:Norbert Perrimon
Name:Mikiko C. Siomi
Name:Haruhiko Siomi
Name:Gregory J. Hannon
Name:Julius Brennecke
Name:Rolando González-José
Name:Kirsty L. Spalding
Name:Jonas Frisén
Name:Peter Arner
Name:Tom W Muir
Name:Eric C Lai
Name:Robert Roeder
Name:Michael Karin
Name:Hannes Raebiger
Name:Alex Zunger
Name:Martin Wille
Name:Douglas A Wiens
Name:Albert László Barabási
Name:Joseph A Mindell
Organizations
Organization:Penn State university

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