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      Structural Basis for Recognition of Ubiquitylated Nucleosome by Dot1L Methyltransferase

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          SUMMARY

          Histone H3 lysine 79 (H3K79) methylation is enriched on actively transcribed genes, and its misregulation is a hallmark of leukemia. Methylation of H3K79, which resides on the structured disk face of the nucleosome, is mediated by the Dot1L methyltransferase. Dot1L activity is part of a trans-histone crosstalk pathway, requiring prior histone H2B ubiquitylation of lysine 120 (H2BK120ub) for optimal activity. However, the molecular details describing both how Dot1L binds to the nucleosome and why Dot1L is activated by H2BK120 ubiquitylation are unknown. Here, we present the cryoelectron microscopy (cryo-EM) structure of Dot1L bound to a nucleosome reconstituted with site-specifically ubiquitylated H2BK120. The structure reveals that Dot1L engages the nucleosome acidic patch using a variant arginine anchor and occupies a conformation poised for methylation. In this conformation, Dot1L and ubiquitin interact directly through complementary hydrophobic surfaces. This study establishes a path to better understand Dot1L function in normal and leukemia cells.

          In Brief

          Dot1L is a histone H3K79-specific methyltransferase that is critical to the pathogenesis of leukemia. Here, Anderson et al. report the cryo-EM structure of Dot1L in complex with a ubiquitylated nucleosome, providing molecular details of how Dot1L binds its nucleosome substrate and is activated by ubiquitin.

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          Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain.

          The N-terminal tails of core histones are subjected to multiple covalent modifications, including acetylation, methylation, and phosphorylation. Similar to acetylation, histone methylation has emerged as an important player in regulating chromatin dynamics and gene activity. Histone methylation occurs on arginine and lysine residues and is catalyzed by two families of proteins, the protein arginine methyltransferase family and the SET-domain-containing methyltransferase family. Here, we report that lysine 79 (K79) of H3, located in the globular domain, can be methylated. K79 methylation occurs in a variety of organisms ranging from yeast to human. In budding yeast, K79 methylation is mediated by the silencing protein DOT1. Consistent with conservation of K79 methylation, DOT1 homologs can be found in a variety of eukaryotic organisms. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. Thus, our studies reveal a new methylation site and define a novel family of histone lysine methyltransferase.
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            The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.

            The covalent modification of nucleosomal histones has emerged as a major determinant of chromatin structure and gene activity. To understand the interplay between various histone modifications, including acetylation and methylation, we performed a genome-wide chromatin structure analysis in a higher eukaryote. We found a binary pattern of histone modifications among euchromatic genes, with active genes being hyperacetylated for H3 and H4 and hypermethylated at Lys 4 and Lys 79 of H3, and inactive genes being hypomethylated and deacetylated at the same residues. Furthermore, the degree of modification correlates with the level of transcription, and modifications are largely restricted to transcribed regions, suggesting that their regulation is tightly linked to polymerase activity.
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              Preparation of nucleosome core particle from recombinant histones.

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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                14 February 2019
                12 February 2019
                27 February 2019
                : 26
                : 7
                : 1681-1690.e5
                Affiliations
                [1 ]Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
                [2 ]Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
                [3 ]Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Department of Health and Human Services, Research Triangle Park, NC 27709, USA
                [4 ]Present address: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
                [5 ]Lead Contact
                Author notes

                AUTHOR CONTRIBUTIONS

                C.J.A. and R.K.M. planned experiments, collected and analyzed data, and prepared the manuscript. M.R.B. and M.J.B. planned experiments, collected and analyzed data, and edited the manuscript. A.H., Y.K., and E.H.B. collected and analyzed data. All authors have commented on and agreed to the content of this manuscript.

                [* ]Correspondence: rmcginty@ 123456email.unc.edu
                Article
                NIHMS1521526
                10.1016/j.celrep.2019.01.058
                6392056
                30759380
                2fb84086-65c5-485f-af6d-894cbffaeb28

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology
                Cell biology

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