Department of Biosciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland.
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
Dev Cell. 2017 Oct 23;43(2):240-252.e5. doi: 10.1016/j.devcel.2017.09.022.
Ribosome biogenesis regulates animal growth and is controlled by nutrient-responsive mTOR signaling. How ribosome biogenesis is regulated during the developmental growth of animals and how nutrient-responsive signaling adjusts ribosome biogenesis in this setting have remained insufficiently understood. We uncover PWP1 as a chromatin-associated regulator of developmental growth with a conserved role in RNA polymerase I (Pol I)-mediated rRNA transcription. We further observed that PWP1 epigenetically maintains the rDNA loci in a transcription-competent state. PWP1 responds to nutrition in Drosophila larvae via mTOR signaling through gene expression and phosphorylation, which controls the nucleolar localization of dPWP1. Our data further imply that dPWP1 acts synergistically with mTOR signaling to regulate the nucleolar localization of TFIIH, a known elongation factor of Pol I. Ribosome biogenesis is often deregulated in cancer, and we demonstrate that high PWP1 levels in human head and neck squamous cell carcinoma tumors are associated with poor prognosis.
核糖体生物发生调节动物生长，受营养感应的 mTOR 信号控制。在动物发育生长过程中，核糖体生物发生是如何被调节的，以及营养感应信号如何在这种情况下调节核糖体生物发生，这些仍然知之甚少。我们发现 PWP1 是一种染色质相关的调控因子，在 RNA 聚合酶 I（Pol I）介导的 rRNA 转录中具有保守作用。我们还观察到，PWP1 通过表观遗传方式将 rDNA 基因座维持在转录活性状态。PWP1 通过 mTOR 信号对果蝇幼虫的营养做出反应，通过基因表达和磷酸化来控制 dPWP1 的核仁定位。我们的数据进一步表明，dPWP1 与 mTOR 信号协同作用，调节 Pol I 的已知延伸因子 TFIIH 的核仁定位。核糖体生物发生在癌症中经常失调，我们证明人类头颈部鳞状细胞癌肿瘤中高水平的 PWP1 与预后不良有关。
