DAZL regulates mRNA deadenylation independently of translation in germ cells
DAZL regulates mRNA deadenylation independently of translation in germ cells
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DOI：
10.1101/2021.02.02.429436
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发表时间：
2021-02
期刊：
影响因子：
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通讯作者：
Richard W. P. Smith;B. Gorgoni;Zoe C. Johnston;William A. Richardson;Kelsey Grieve;Ross C. Anderson;N. Gray
中科院分区：
文献类型：
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作者：
Richard W. P. Smith;B. Gorgoni;Zoe C. Johnston;William A. Richardson;Kelsey Grieve;Ross C. Anderson;N. Gray
配子发生过程中的异常基因表达是导致不育的因素之一，影响着全球约15%的夫妇。无精子症样缺失基因（Deleted-in-Azospermia-Like，DAZL）是DAZ基因家族的一员，编码一种mRNA特异性的翻译调节因子，在两性配子发生中起重要作用。在这项研究中，我们表明，DAZL控制卵母细胞中的基因表达，通过调节mRNA聚（A）尾的长度，时间和扩增的基因调控在生殖细胞中，其中基因表达完全转录后调节的主要决定因素。我们发现，DAZL不诱导聚腺苷酸化，但DAZL的结合有效地抑制卵母细胞成熟诱导的mRNA去腺苷酸化。我们发现，这种活性依赖于DAZL介导的聚（A）结合蛋白，PABP，mRNA的招聘。虽然DAZL也通过PABP募集激活mRNA翻译，但机制分析显示，DAZL稳定poly（A）尾既不需要翻译也不需要翻译激活，这表明DAZL-PABP复合物具有两种相互独立的转录后作用。我们发现，招募的PABP必须保持其结合RNA的能力，从而导致DAZL招募PABP和/或稳定PABP与poly（A）结合的模型，从而防止deadenylases的进入。这些结果表明，DAZL在调节生殖细胞mRNA命运中的作用比以前认为的更复杂，并告知mRNA翻译和去腺苷化之间的联系知之甚少，表明它们可以在机械上分离。
Aberrant gene expression during gametogenesis is one of the factors underlying infertility, which affects roughly 15% of couples worldwide. Deleted-in-Azoospermia-Like (DAZL), a member of the DAZ-gene family, encodes an mRNA-specific regulator of translation which is essential for gametogenesis in both sexes. In this study we show that DAZL controls gene expression in oocytes by regulating the length of the mRNA poly(A) tail, a major determinant of temporal and amplitudinal gene regulation in germ cells, in which gene expression is regulated entirely post-transcriptionally. We show that DAZL does not induce polyadenylation but that binding of DAZL efficiently inhibits mRNA deadenylation induced by oocyte maturation. We reveal that this activity depends on DAZL-mediated recruitment of poly(A)-binding protein, PABP, to the mRNA. Although DAZL also activates mRNA translation via PABP recruitment, mechanistic analysis revealed that neither translation nor translational activation are required for DAZL to stabilise the poly(A) tail, suggesting two mutually independent posttranscriptional roles for the DAZL-PABP complex. We show that recruited PABP must maintain its ability to bind RNA, leading to a model in which DAZL recruits PABP and/or stabilises PABP binding to poly(A) thereby preventing access of deadenylases. These results indicate that the role of DAZL in regulating germ-cell mRNA fate is more complex than previously thought and inform on the poorly understood links between mRNA translation and deadenylation, showing that they can be mechanistically separable.