DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs.
DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs.
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DOI：
10.1038/nature21690
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发表时间：
2017-03-23
期刊：
影响因子：
64.8
通讯作者：
Tuschl T
中科院分区：
文献类型：
--
作者：
Yamaji M;Jishage M;Meyer C;Suryawanshi H;Der E;Yamaji M;Garzia A;Morozov P;Manickavel S;McFarland HL;Roeder RG;Hafner M;Tuschl T
脊椎动物保守的RNA结合蛋白（RBP）DND 1是原始生殖细胞（PGCs）存活所必需的，也是小鼠生殖细胞肿瘤（TGCT）抑制所必需的。在这里，我们报告DND 1主要在信使RNA（mRNA）3′非翻译区（UTR）结合UU[A/U]三核苷酸基序，并通过直接募集CCR 4-NOT去腺苷酶（CCR 4）复合物使靶mRNA不稳定。转录组学分析表明，抑制的程度取决于DND 1结合位点的数量。DND 1依赖的mRNA失稳是通过抑制凋亡来维持小鼠PGCs和精原干细胞（SSC）存活所必需的。靶RNA谱包括细胞凋亡、炎症的正调节因子和调节干细胞多能性的信号传导途径的调节因子，包括TGF-β超家族，所有这些在Dnd 1缺陷型PGC中异常升高。我们建议，诱导的转录后抑制因子DND 1协同与并发的转录变化，以提高细胞分化和生殖细胞的维护过程中的发育转变。
The vertebrate-conserved RNA-binding protein (RBP) DND1 is required for survival of primordial germ cells (PGCs), as well as germ cell tumour (TGCT) suppression in mice. Here we report that DND1 binds a UU[A/U] trinucleotide motif predominantly in messenger RNA (mRNA) 3′ untranslated regions (UTRs), and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase (CCR4) complex. Transcriptomic analysis revealed that the extent of suppression is dependent on the number of DND1 binding sites. The DND1-dependent mRNA destabilization is required for survival of murine PGCs and spermatogonial stem cells (SSCs) by suppressing apoptosis. The target RNA spectrum includes positive regulators of apoptosis, inflammation, and modulators of signalling pathways regulating stem cell pluripotency including the TGF-β super family, all of which are aberrantly elevated in Dnd1-deficient PGCs. We propose that the induction of the posttranscriptional suppressor DND1 synergizes with concurrent transcriptional changes to sharpen developmental transitions during cellular differentiation and maintenance of the germline.