Title | Evidence that ubiquitylated H2B corrals hDot1L on the nucleosomal surface to induce H3K79 methylation. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Zhou, L, Holt, MT, Ohashi, N, Zhao, A, Müller, MM, Wang, B, Muir, TW |
Journal | Nat Commun |
Volume | 7 |
Pagination | 10589 |
Date Published | 2016 Feb 02 |
ISSN | 2041-1723 |
Keywords | Gene Expression Regulation, Enzymologic, Histone-Lysine N-Methyltransferase, Histones, Humans, Methylation, Methyltransferases, Models, Molecular, Nucleosomes, Protein Binding, Protein Conformation, Ubiquitinated Proteins |
Abstract | <p>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. </p> |
DOI | 10.1038/ncomms10589 |
Alternate Journal | Nat Commun |
PubMed ID | 26830124 |
PubMed Central ID | PMC4740876 |
Grant List | R01 GM107047 / GM / NIGMS NIH HHS / United States R37 GM086868 / GM / NIGMS NIH HHS / United States R37-GM086868 / GM / NIGMS NIH HHS / United States |