Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome

Yasuhiro Arimura, Masae Ikura, Risa Fujita, Mamiko Noda, Wataru Kobayashi, Naoki Horikoshi, Jiying Sun, Lin Shi, Masayuki Kusakabe, Masahiko Harata, Yasuyuki Ohkawa, Satoshi Tashiro, Hiroshi Kimura, Tsuyoshi Ikura, Hitoshi Kurumizaka

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    Abstract

    Mutations of the Glu76 residue of canonical histone H2B are frequently found in cancer cells. However, it is quite mysterious how a single amino acid substitution in one of the multiple H2B genes affects cell fate. Here we found that the H2B E76K mutation, in which Glu76 is replaced by Lys (E76K), distorted the interface between H2B and H4 in the nucleosome, as revealed by the crystal structure and induced nucleosome instability in vivo and in vitro. Exogenous production of the H2B E76K mutant robustly enhanced the colony formation ability of the expressing cells, indicating that the H2B E76K mutant has the potential to promote oncogenic transformation in the presence of wild-type H2B. We found that other cancer-associated mutations of histones, H3.1 E97K and H2A.Z.1 R80C, also induced nucleosome instability. Interestingly, like the H2B E76K mutant, the H3.1 E97K mutant was minimally incorporated into chromatin in cells, but it enhanced the colony formation ability. In contrast, the H2A.Z.1 R80C mutant was incorporated into chromatin in cells, and had minor effects on the colony formation ability of the cells. These characteristics of histones with cancer-associated mutations may provide important information toward understanding how the mutations promote cancer progression.

    Original languageEnglish
    Pages (from-to)10007-10018
    Number of pages12
    JournalNucleic Acids Research
    Volume46
    Issue number19
    DOIs
    Publication statusPublished - 2018 Nov 2

    Fingerprint

    Nucleosomes
    Histones
    Mutation
    Neoplasms
    Chromatin
    Amino Acid Substitution
    Genes

    ASJC Scopus subject areas

    • Genetics

    Cite this

    Arimura, Y., Ikura, M., Fujita, R., Noda, M., Kobayashi, W., Horikoshi, N., ... Kurumizaka, H. (2018). Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome. Nucleic Acids Research, 46(19), 10007-10018. https://doi.org/10.1093/nar/gky661

    Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome. / Arimura, Yasuhiro; Ikura, Masae; Fujita, Risa; Noda, Mamiko; Kobayashi, Wataru; Horikoshi, Naoki; Sun, Jiying; Shi, Lin; Kusakabe, Masayuki; Harata, Masahiko; Ohkawa, Yasuyuki; Tashiro, Satoshi; Kimura, Hiroshi; Ikura, Tsuyoshi; Kurumizaka, Hitoshi.

    In: Nucleic Acids Research, Vol. 46, No. 19, 02.11.2018, p. 10007-10018.

    Research output: Contribution to journalArticle

    Arimura, Y, Ikura, M, Fujita, R, Noda, M, Kobayashi, W, Horikoshi, N, Sun, J, Shi, L, Kusakabe, M, Harata, M, Ohkawa, Y, Tashiro, S, Kimura, H, Ikura, T & Kurumizaka, H 2018, 'Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome', Nucleic Acids Research, vol. 46, no. 19, pp. 10007-10018. https://doi.org/10.1093/nar/gky661
    Arimura, Yasuhiro ; Ikura, Masae ; Fujita, Risa ; Noda, Mamiko ; Kobayashi, Wataru ; Horikoshi, Naoki ; Sun, Jiying ; Shi, Lin ; Kusakabe, Masayuki ; Harata, Masahiko ; Ohkawa, Yasuyuki ; Tashiro, Satoshi ; Kimura, Hiroshi ; Ikura, Tsuyoshi ; Kurumizaka, Hitoshi. / Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome. In: Nucleic Acids Research. 2018 ; Vol. 46, No. 19. pp. 10007-10018.
    @article{7f011079e9b142f6ba3cfd6068b76828,
    title = "Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome",
    abstract = "Mutations of the Glu76 residue of canonical histone H2B are frequently found in cancer cells. However, it is quite mysterious how a single amino acid substitution in one of the multiple H2B genes affects cell fate. Here we found that the H2B E76K mutation, in which Glu76 is replaced by Lys (E76K), distorted the interface between H2B and H4 in the nucleosome, as revealed by the crystal structure and induced nucleosome instability in vivo and in vitro. Exogenous production of the H2B E76K mutant robustly enhanced the colony formation ability of the expressing cells, indicating that the H2B E76K mutant has the potential to promote oncogenic transformation in the presence of wild-type H2B. We found that other cancer-associated mutations of histones, H3.1 E97K and H2A.Z.1 R80C, also induced nucleosome instability. Interestingly, like the H2B E76K mutant, the H3.1 E97K mutant was minimally incorporated into chromatin in cells, but it enhanced the colony formation ability. In contrast, the H2A.Z.1 R80C mutant was incorporated into chromatin in cells, and had minor effects on the colony formation ability of the cells. These characteristics of histones with cancer-associated mutations may provide important information toward understanding how the mutations promote cancer progression.",
    author = "Yasuhiro Arimura and Masae Ikura and Risa Fujita and Mamiko Noda and Wataru Kobayashi and Naoki Horikoshi and Jiying Sun and Lin Shi and Masayuki Kusakabe and Masahiko Harata and Yasuyuki Ohkawa and Satoshi Tashiro and Hiroshi Kimura and Tsuyoshi Ikura and Hitoshi Kurumizaka",
    year = "2018",
    month = "11",
    day = "2",
    doi = "10.1093/nar/gky661",
    language = "English",
    volume = "46",
    pages = "10007--10018",
    journal = "Nucleic Acids Research",
    issn = "0305-1048",
    publisher = "Oxford University Press",
    number = "19",

    }

    TY - JOUR

    T1 - Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome

    AU - Arimura, Yasuhiro

    AU - Ikura, Masae

    AU - Fujita, Risa

    AU - Noda, Mamiko

    AU - Kobayashi, Wataru

    AU - Horikoshi, Naoki

    AU - Sun, Jiying

    AU - Shi, Lin

    AU - Kusakabe, Masayuki

    AU - Harata, Masahiko

    AU - Ohkawa, Yasuyuki

    AU - Tashiro, Satoshi

    AU - Kimura, Hiroshi

    AU - Ikura, Tsuyoshi

    AU - Kurumizaka, Hitoshi

    PY - 2018/11/2

    Y1 - 2018/11/2

    N2 - Mutations of the Glu76 residue of canonical histone H2B are frequently found in cancer cells. However, it is quite mysterious how a single amino acid substitution in one of the multiple H2B genes affects cell fate. Here we found that the H2B E76K mutation, in which Glu76 is replaced by Lys (E76K), distorted the interface between H2B and H4 in the nucleosome, as revealed by the crystal structure and induced nucleosome instability in vivo and in vitro. Exogenous production of the H2B E76K mutant robustly enhanced the colony formation ability of the expressing cells, indicating that the H2B E76K mutant has the potential to promote oncogenic transformation in the presence of wild-type H2B. We found that other cancer-associated mutations of histones, H3.1 E97K and H2A.Z.1 R80C, also induced nucleosome instability. Interestingly, like the H2B E76K mutant, the H3.1 E97K mutant was minimally incorporated into chromatin in cells, but it enhanced the colony formation ability. In contrast, the H2A.Z.1 R80C mutant was incorporated into chromatin in cells, and had minor effects on the colony formation ability of the cells. These characteristics of histones with cancer-associated mutations may provide important information toward understanding how the mutations promote cancer progression.

    AB - Mutations of the Glu76 residue of canonical histone H2B are frequently found in cancer cells. However, it is quite mysterious how a single amino acid substitution in one of the multiple H2B genes affects cell fate. Here we found that the H2B E76K mutation, in which Glu76 is replaced by Lys (E76K), distorted the interface between H2B and H4 in the nucleosome, as revealed by the crystal structure and induced nucleosome instability in vivo and in vitro. Exogenous production of the H2B E76K mutant robustly enhanced the colony formation ability of the expressing cells, indicating that the H2B E76K mutant has the potential to promote oncogenic transformation in the presence of wild-type H2B. We found that other cancer-associated mutations of histones, H3.1 E97K and H2A.Z.1 R80C, also induced nucleosome instability. Interestingly, like the H2B E76K mutant, the H3.1 E97K mutant was minimally incorporated into chromatin in cells, but it enhanced the colony formation ability. In contrast, the H2A.Z.1 R80C mutant was incorporated into chromatin in cells, and had minor effects on the colony formation ability of the cells. These characteristics of histones with cancer-associated mutations may provide important information toward understanding how the mutations promote cancer progression.

    UR - http://www.scopus.com/inward/record.url?scp=85056260677&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85056260677&partnerID=8YFLogxK

    U2 - 10.1093/nar/gky661

    DO - 10.1093/nar/gky661

    M3 - Article

    VL - 46

    SP - 10007

    EP - 10018

    JO - Nucleic Acids Research

    JF - Nucleic Acids Research

    SN - 0305-1048

    IS - 19

    ER -