• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Automethylation-induced conformational switch in Clr4 (Suv39h) maintains epigenetic stability
【24h】

Automethylation-induced conformational switch in Clr4 (Suv39h) maintains epigenetic stability

机译：自动甲基化诱导的Clr4（Suv39h）构象转换保持表观遗传稳定性

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Histone H3 lysine 9 methylation (H3K9me) mediates heterochromatic gene silencing and is important for genome stability and the regulation of gene expression(1-4). The establishment and epigenetic maintenance of heterochromatin involve the recruitment of H3K9 methyltransferases to specific sites on DNA, followed by the recognition of pre-existing H3K9me by the methyltransferase and methylation of proximal histone H3(5-11). This positive feedback loop must be tightly regulated to prevent deleterious epigenetic gene silencing. Extrinsic anti-silencing mechanisms involving histone demethylation or boundary elements help to limit the spread of inappropriate H3K9me(12-15). However, how H3K9 methyltransferase activity is locally restricted or prevented from initiating random H3K9me-which would lead to aberrant gene silencing and epigenetic instability-is not fully understood. Here we reveal an autoinhibited conformation in the conserved H3K9 methyltransferase Clr4 (also known as Suv39h) of the fission yeast Schizosaccharomyces pombe that has a critical role in preventing aberrant heterochromatin formation. Biochemical and X-ray crystallographic data show that an internal loop in Clr4 inhibits the catalytic activity of this enzyme by blocking the histone H3K9 substrate-binding pocket, and that automethylation of specific lysines in this loop promotes a conformational switch that enhances the H3K9me activity of Clr4. Mutations that are predicted to disrupt this regulation lead to aberrant H3K9me, loss of heterochromatin domains and inhibition of growth, demonstrating the importance of the intrinsic inhibition and auto-activation of Clr4 in regulating the deposition of H3K9me and in preventing epigenetic instability. Conservation of the Clr4 autoregulatory loop in other H3K9 methyltransferases and the automethylation of a corresponding lysine in the human SUV39H2 homologue(16) suggest that the mechanism described here is broadly conserved.
机译：组蛋白H3赖氨酸9甲基化（H3K9me）介导异色基因沉默，对于基因组稳定性和基因表达的调节具有重要意义（1-4）。异染色质的建立和表观遗传维护涉及将H3K9甲基转移酶募集到DNA上的特定位点，然后通过甲基转移酶和近端组蛋白H3（5-11）的甲基化识别已存在的H3K9me。必须严格调节此正反馈回路，以防止有害的表观遗传基因沉默。涉及组蛋白去甲基化或边界元素的外部抗沉默机制有助于限制不适当的H3K9me（12-15）的扩散。但是，如何完全限制或防止H3K9甲基转移酶活性局部引发或阻止随机H3K9me的启动，这将导致异常的基因沉默和表观遗传不稳定。在这里，我们揭示了裂殖酵母粟酒裂殖酵母中保守的H3K9甲基转移酶Clr4（也称为Suv39h）中的自抑制构象，它在防止异常异染色质形成中起关键作用。生化和X射线晶体学数据显示，Clr4的内部环通过阻断组蛋白H3K9底物结合口袋而抑制了该酶的催化活性，并且该环中特定赖氨酸的自甲基化促进了构象转换，从而增强了H3K9me的活性。 Clr4。预计会破坏该调控的突变会导致H3K9me异常，异染色质结构域丢失和生长抑制，这表明在抑制H3K9me沉积和防止表观遗传不稳定中，Clr4的内在抑制和自动激活很重要。在其他H3K9甲基转移酶中Clr4自调节环的保守和人类SUV39H2同源物中相应赖氨酸的自甲基化（16）提示，这里描述的机制是广泛保守的。

著录项

  • 来源
    《Nature》 |2018年第7719期|504-508|共5页
  • 作者

    Iglesias Nahid; Currie Mark A.; Jih Gloria; Paulo Joao A.; Siuti Nertila; Kalocsay Marian; Gygi Steven P.; Moazed Danesh;

  • 作者单位

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号