Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.
Biozentrum, University of Basel, 4056 Basel, Switzerland.
Int J Mol Sci. 2022 Jun 13;23(12):6592. doi: 10.3390/ijms23126592.
Nanos RNA-binding proteins are critical factors of germline development throughout the animal kingdom and their dysfunction causes infertility. During evolution, mammalian Nanos paralogues adopted divergent roles in germ cell biology. However, the molecular basis behind this divergence, such as their target mRNAs, remains poorly understood. Our RNA-sequencing analysis in a human primordial germ cell model-TCam-2 cell line revealed distinct pools of genes involved in the cell cycle process downregulated upon NANOS1 and NANOS3 overexpression. We show that NANOS1 and NANOS3 proteins influence different stages of the cell cycle. Namely, NANOS1 is involved in the G1/S and NANOS3 in the G2/M phase transition. Many of their cell cycle targets are known infertility and cancer-germ cell genes. Moreover, NANOS3 in complex with RNA-binding protein PUM1 causes 3'UTR-mediated repression of mRNA encoding a transcription factor crucial for G2/M phase transition. Interestingly, while NANOS3 and PUM1 act as post-transcriptional repressors of FOXM1, FOXM1 potentially acts as a transcriptional activator of NANOS3, PUM1, and itself. Finally, by utilizing publicly available RNA-sequencing datasets, we show that the balance between FOXM1-NANOS3 and FOXM1-PUM1 expression levels is disrupted in testis cancer, suggesting a potential role in this disease.
纳米 RNA 结合蛋白是整个动物界生殖系发育的关键因素，其功能障碍导致不孕。在进化过程中，哺乳动物 Nanos 同源物在生殖细胞生物学中发挥了不同的作用。然而，这种分化的分子基础，如它们的靶 mRNA，仍然知之甚少。我们在人类原始生殖细胞模型-TCam-2 细胞系中的 RNA 测序分析表明，参与细胞周期过程的基因库在 NANOS1 和 NANOS3 过表达时下调。我们表明，NANOS1 和 NANOS3 蛋白影响细胞周期的不同阶段。具体来说，NANOS1 参与 G1/S 期，而 NANOS3 参与 G2/M 期过渡。它们的许多细胞周期靶标是已知的不孕和癌症生殖细胞基因。此外，NANOS3 与 RNA 结合蛋白 PUM1 形成复合物，导致编码对 G2/M 期过渡至关重要的转录因子的 mRNA 发生 3'UTR 介导的抑制。有趣的是，虽然 NANOS3 和 PUM1 作为 FOXM1 的转录后抑制剂，但 FOXM1 可能作为 FOXM1-NANOS3 和 FOXM1-PUM1 表达水平平衡在睾丸癌中被打破，提示其在这种疾病中可能具有潜在作用。
