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A role for the Perlman syndrome exonuclease Dis312in the Lin28-let-7 pathway

机译：Perlman综合征核酸外切酶Dis312在Lin28-let-7途径中的作用

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摘要

The pluripotency factor Lin28 blocks the expression of let-7 microRNAs in undifferentiated cells during development, and functions as an oncogene in a subset of cancers~1. Lin28 binds to let-7 precursor (pre-let-7) RNAs and recruits 3' terminal uridylyl transferases to selectively inhibit let-7 biogenesis~(2-4). Uridylated pre-let-7 is refractory to processing by Dicer, and is rapidly degraded by an unknown RNase~5. Here we identify Dis3l2 as the 3'-5' exonuclease responsible for the decay of uridylated pre-let-7 in mouse embryonic stem cells. Biochemical reconstitution assays show that 3' oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis312 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3' oligouridylation as an RNA decay signal for Dis312, and identifies the first physiological RNA substrate of this new exonuclease, which is mutated in the Perlman syndrome of fetal overgrowth and causes a predisposition to Wilms' tumour development~6.
机译：多能性因子Lin28在发育过程中阻断let-7 microRNA在未分化细胞中的表达，并在约1种癌症的子集中起癌基因的作用。 Lin28与let-7前体（pre-let-7）RNA结合，并募集3'末端尿嘧啶转移酶以选择性抑制let-7生物发生〜（2-4）。 Uridylated pre-let-7对Dicer难以加工，并被未知的RNase〜5迅速降解。在这里，我们确定Dis3l2为3'-5'核酸外切酶，负责小鼠胚胎干细胞中尿嘧啶化的pre-let-7的降解。生化重建分析表明3'寡糖基化可在体外刺激Dis3l2活性，而在小鼠胚胎干细胞中Dis312的敲低可导致pre-let-7的稳定。我们的研究将3'寡聚尿苷酸化为Dis312的RNA衰减信号，并鉴定出这种新的核酸外切酶的第一个生理RNA底物，该底物在胎儿过度生长的Perlman综合征中发生突变，并导致Wilms的肿瘤发展易感性[6]。

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  • 来源
    《Nature》 |2013年第7448期|244-248|共5页
  • 作者

    Hao-Ming Chang; Robinson Triboulet; James E. Thornton; Richard I. Gregory;

  • 作者单位

    Stem Cell Program, Boston Children's Hospital, Massachusetts 02115, USA,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115,USA,Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA;

    Stem Cell Program, Boston Children's Hospital, Massachusetts 02115, USA,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115,USA,Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA;

    Stem Cell Program, Boston Children's Hospital, Massachusetts 02115, USA,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115,USA,Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA;

    Stem Cell Program, Boston Children's Hospital, Massachusetts 02115, USA,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115,USA,Harvard Stem Cell Institute, Boston, Massachusetts 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);
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