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Uhrf1 - dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication

机译：依赖Uhrf1的H3K23泛素化偶联维持DNA甲基化和复制

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摘要

"环指域蛋白"Uhrf1通过将DNA甲基转移酶 Dnmtl吸纳到半甲基化的DNA点上而在复制期间在维持DNA甲基化的模式中起必不可少的作用。在这项研究中，Makoto Nakanishi及同事利用蟾蜍卵提取物在一个试管系统中重现了DNA甲基化的维持。他们发现，Uhrf1是组蛋白H3的一个E3"泛素连接酶",H3的"泛素化"是Dnmt1向DNA复制点的吸纳所必需的。%Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. Although it is well established that Uhrfl (ubiquitin-like with PHD and ring finger domains 1; also known as Np95 and ICBP90) specifically binds to hemi-methylated DNA through its SRA (SET and RING finger associated) domain and has an essential role in maintenance of DNA methylation by recruiting Dnmtl to hemi-methylated DNA sites, the mechanism by which Uhrf1 coordinates the maintenance of DNA methylation and DNA replication is largely unknown. Here we show that Uhrf1 -dependent histone H3 ubiquitylation has a prerequisite role in the maintenance DNA methylation. Using Xenopus egg extracts, we successfully reproduce maintenance DNA methylation in vitro. Dnmt1 depletion results in a marked accumulation of Uhrf1 -dependent ubiquitylation of histone H3 at lysine 23. Dnmt1 preferentially associates with ubiquitylated H3 in vitro though a region previously identified as a replication foci targeting sequence. The RING finger mutant of Uhrfl fails to recruit Dnmtl to DNA replication sites and maintain DNA methylation in mammalian cultured cells. Our findings represent the first evidence, to our knowledge, of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.
机译："环指域蛋白"Uhrf1通过将DNA甲基转移酶 Dnmtl吸纳到半甲基化的DNA点上而在复制期间在维持DNA甲基化的模式中起必不可少的作用。在这项研究中，Makoto Nakanishi及同事利用蟾蜍卵提取物在一个试管系统中重现了DNA甲基化的维持。他们发现，Uhrf1是组蛋白H3的一个E3"泛素连接酶",H3的"泛素化"是Dnmt1向DNA复制点的吸纳所必需的。%Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. Although it is well established that Uhrfl (ubiquitin-like with PHD and ring finger domains 1; also known as Np95 and ICBP90) specifically binds to hemi-methylated DNA through its SRA (SET and RING finger associated) domain and has an essential role in maintenance of DNA methylation by recruiting Dnmtl to hemi-methylated DNA sites, the mechanism by which Uhrf1 coordinates the maintenance of DNA methylation and DNA replication is largely unknown. Here we show that Uhrf1 -dependent histone H3 ubiquitylation has a prerequisite role in the maintenance DNA methylation. Using Xenopus egg extracts, we successfully reproduce maintenance DNA methylation in vitro. Dnmt1 depletion results in a marked accumulation of Uhrf1 -dependent ubiquitylation of histone H3 at lysine 23. Dnmt1 preferentially associates with ubiquitylated H3 in vitro though a region previously identified as a replication foci targeting sequence. The RING finger mutant of Uhrfl fails to recruit Dnmtl to DNA replication sites and maintain DNA methylation in mammalian cultured cells. Our findings represent the first evidence, to our knowledge, of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.

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  • 来源
    《Nature》 |2013年第7470期|249-253b3|共6页
  • 作者

    Atsuya Nishiyama; Luna Yamaguchi; Jafar Sharif; Yoshikazu Johmura; Takeshi Kawamura; Keiko Nakanishi; Shintaro Shimamura; Kyohei Arita; Tatsuhiko Kodama; Fuyuki Ishikawa; Haruhiko Koseki; Makoto Nakanishi;

  • 作者单位

    Department of Cell Biology.Graduate School,Nagoya City University,1Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;

    Department of Cell Biology.Graduate School,Nagoya City University,1Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;

    RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan;

    Department of Cell Biology.Graduate School,Nagoya City University,1Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;

    Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan;

    Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya-cho, Kasugai, Aichi 480-0392, Japan;

    Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan;

    Graduate School of Medical Life Sciences, Yokohama City University, 1-7-29, Suehiro-cho.Tsurumi -ku, Yokohama 230-0045, Japan;

    Laboratory for System Biology and Medicine, RCAST, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan;

    Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;

    RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan;

    Department of Cell Biology.Graduate School,Nagoya City University,1Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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