1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Cryo-EM structure of SETD2/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Substitution of lysine 36 with methionine in histone H3.3 (H3.3K36M) is an oncogenic mutation that inhibits SETD2-mediated histone H3K36 tri-methylation in tumors. To investigate how the oncohistone mutation affects the function of SETD2 at the nucleosome level, we determined the cryo-EM structure of human SETD2 associated with an H3.3K36M nucleosome and cofactor S-adenosylmethionine (SAM), and revealed that SETD2 is attached to the N-terminal region of histone H3 and the nucleosome DNA at superhelix location 1, accompanied with the partial unwrapping of nucleosome DNA to expose the SETD2-binding site. These structural features were also observed in the previous cryo-EM structure of the fungal Set2–nucleosome complex. By contrast with the stable association of SETD2 with the H3.3K36M nucleosome, the EM densities of SETD2 could not be observed on the wild-type nucleosome surface, suggesting that the association of SETD2 with wild-type nucleosome might be transient. The linker histone H1, which stabilizes the wrapping of nucleosome DNA at the entry/exit sites, exhibits an inhibitory effect on the activities of SETD2 and displays inversely correlated genome distributions with that of the H3K36me3 marks. Cryo-EM analysis of yeast H3K36 methyltransferase Set2 complexed with nucleosomes further revealed evolutionarily conserved structural features for nucleosome recognition in eukaryotes, and provides insights into the mechanism of activity regulation. These findings have advanced our understanding of the structural basis for the tumorigenesis mechanism of the H3.3K36M mutation and highlight the effect of nucleosome conformation on the regulation of histone modification.

          Related collections

          Most cited references 66

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Fast gapped-read alignment with Bowtie 2.

            As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              UCSF Chimera--a visualization system for exploratory research and analysis.

              The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
                Bookmark

                Author and article information

                Contributors
                dfang@zju.edu.cn
                huangjing@shsmu.edu.cn
                Journal
                Cell Discov
                Cell Discov
                Cell Discovery
                Springer Singapore (Singapore )
                2056-5968
                11 May 2021
                11 May 2021
                2021
                : 7
                Affiliations
                [1 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Ninth People’s Hospital, , Shanghai Jiao Tong University School of Medicine, ; Shanghai, 200125 China
                [2 ]Shanghai Institute of Precision Medicine, Shanghai, 200125 China
                [3 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, State Key Laboratory of Oncogenes and Related Genes, , Shanghai Jiao Tong University School of Medicine, ; Shanghai, 200125 China
                [4 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Life Sciences Institute, , Zhejiang University, ; Hangzhou, Zhejiang 310058 China
                [5 ]GRID grid.410726.6, ISNI 0000 0004 1797 8419, State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, , University of Chinese Academy of Sciences, Chinese Academy of Sciences, ; Shanghai, 201210 China
                [6 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People’s Hospital, , Shanghai Jiao Tong University School of Medicine, ; Shanghai, 200011 China
                [7 ]National Clinical Research Center for Oral Diseases, Shanghai, 200011 China
                [8 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, ; Shanghai, 200011 China
                [9 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, School of Life Sciences and Biotechnology, , Shanghai Jiao Tong University, ; Shanghai, 200240 China
                Article
                261
                10.1038/s41421-021-00261-6
                8110526
                33972509
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                cryoelectron microscopy, epigenetics

                Comments

                Comment on this article