Article abstract
Nature Structural & Molecular Biology 15, 550 - 557 (2008)
Published online: 30 May 2008 | doi:10.1038/nsmb.1432
Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states
Floor Frederiks1, Manuel Tzouros2, Gideon Oudgenoeg2, Tibor van Welsem1, Maarten Fornerod3, Jeroen Krijgsveld2 & Fred van Leeuwen1
Abstract
Whereas mono-, di- and trimethylation states of lysines on histones typically have specific functions, no specific functions have been attributed so far to the different methylation states of histone H3 Lysine 79 (H3K79) generated by Dot1. Here we show that Dot1, in contrast to other known histone methyltransferases, introduces multiple methyl groups via a nonprocessive mechanism. The kinetic mechanism implies that the H3K79 methylation states cannot be generated independently, suggesting functional redundancy. Indeed, gene silencing in yeast, which is dependent on Dot1, relied on global H3K79 methylation levels and not on one specific methylation state. Furthermore, our findings suggest that histone H2B ubiquitination affects H3K79 trimethylation by enhancing synthesis of all H3K79 methylation states. Our results suggest that multiple methylation of H3K79 leads to a binary code, which is expected to limit the possibilities for regulation by putative demethylases or binding proteins.
- Division of Cellular Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
- Department of Biomolecular Mass Spectrometry, Faculty of Science, Utrecht University, Sorbonnelaan 16, Utrecht, 3584 CA, The Netherlands.
- Division of Tumor Biology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
Correspondence to: Fred van Leeuwen1 e-mail: fred.v.leeuwen@nki.nl
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