In the last decade, several novel functions of the mammalian Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) have been discovered, going far beyond its canonical function as DNA repair enzyme and unveiling its potential roles in cancer development. Indeed, it was shown to be involved in DNA G-quadruplex biology and RNA metabolism, most importantly in the miRNA maturation pathway and the decay of oxidized or abasic miRNAs during oxidative stress conditions. In recent years, several noncanonical pathways of miRNA biogenesis have emerged, with a specific focus on guanosine-rich precursors that can form RNA G-quadruplex (rG4) structures. Here, we show that several miRNA precursors, dysregulated upon APE1 depletion, contain an rG4 motif and that their corresponding target genes are up-regulated after APE1 depletion. We also demonstrate, both by in vitro assays and by using different cancer cell lines, that APE1 can modulate the folding of an rG4 structure contained in pre-miR-92b, with a mechanism strictly dependent on lysine residues present in its N-terminal disordered region. Furthermore, APE1 cellular depletion alters the maturation process of miR-92b, mainly affecting the shuttling between the nucleus and cytosol. Bioinformatic analysis of APE1-regulated rG4-containing miRNAs supports the relevance of our findings in cancer biology. Specifically, these miRNAs exhibit high prognostic significance in lung, cervical, and liver tumors, as suggested by their involvement in several cancer-related pathways.

中文翻译：

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脱嘌呤/脱嘧啶核酸内切酶 1 调节 miR-92b 的 RNA G-四链体折叠并控制其在癌细胞中的表达


在过去的十年中，已经发现了哺乳动物 Apurinic/Apyrimidinic Endodeoxyribonuclease 1 （APE1） 的几种新功能，远远超出了其作为 DNA 修复酶的经典功能，并揭示了它在癌症发展中的潜在作用。事实上，它被证明参与 DNA G-四链体生物学和 RNA 代谢，最重要的是参与 miRNA 成熟途径和氧化应激条件下氧化或无碱基 miRNA 的衰变。近年来，出现了几种 miRNA 生物发生的非经典途径，特别关注可以形成 RNA G-四链体 （rG4） 结构的富含鸟苷的前体。在这里，我们表明，在 APE1 耗竭时失调的几种 miRNA 前体包含一个 rG4 基序，并且它们相应的靶基因在 APE1 耗竭后上调。我们还通过体外测定和使用不同的癌细胞系证明，APE1 可以调节 pre-miR-92b 中包含的 rG4 结构的折叠，其机制严格依赖于存在于其 N 末端无序区域的赖氨酸残基。此外，APE1 细胞耗竭会改变 miR-92b 的成熟过程，主要影响细胞核和胞质溶胶之间的穿梭。对 APE1 调节的含 rG4 的 miRNA 的生物信息学分析支持我们在癌症生物学中的发现的相关性。具体来说，这些 miRNA 在肺、宫颈和肝脏肿瘤中表现出很高的预后意义，正如它们参与几种癌症相关途径所表明的那样。