三链DNA-RNA三链体杂交涉及多种生物过程，包括基因表达调控、DNA修复和染色体稳定性。然而，肿瘤发生背后的 DNA-RNA 三链体介导机制仍有待充分阐明。在这里，我们发现肽基脯氨酰异构酶 A (PPIA) 作为锚定点，通过与 GAU1 的外显子 4 相互作用来招募 GAU1 lncRNA，并增强 SENP5/GAU1 DNA-lncRNA 三链体的形成。有趣的是，GAU1 外显子 3 的 TFR4 区域和 SENP5 启动子 DNA 的 TTS4 区域构成了形成 SENP5/GAU1 三链体的片段。 SENP5/GAU1 三链体随后触发甲基转移酶 SET1A 招募到 GAU1 的外显子 1，导致 H3K4 三甲基化的富集和 SENP5 转录的激活，从而在体外和体内驱动胃癌的肿瘤发生。我们的研究揭示了肿瘤发生中 PPIA 引导的 SENP5/GAU1 DNA-lncRNA 三链体形成的机制，并提供了异构酶辅助 DNA-RNA 杂交动力学的概念。© 2024。作者。

The three-stranded DNA-RNA triplex hybridization is involved in various biological processes, including gene expression regulation, DNA repair, and chromosomal stability. However, the DNA-RNA triplex mediating mechanisms underlying tumorigenesis remain to be fully elucidated. Here, we show that peptidylprolyl isomerase A (PPIA) serves as anchor to recruit GAU1 lncRNA by interacting with exon 4 of GAU1 and enhances the formation of SENP5/GAU1 DNA-lncRNA triplex. Intriguingly, TFR4 region of GAU1 exon 3 and TTS4 region of SENP5 promoter DNA constitute fragments forming the SENP5/GAU1 triplex. The SENP5/GAU1 triplex subsequently triggers the recruitment of the methyltransferase SET1A to exon 1 of GAU1, leading to the enrichment of H3K4 trimethylation and the activation of SENP5 transcription for driving the tumorigenesis of gastric cancer in vitro and in vivo. Our study reveals a mechanism of PPIA-guided SENP5/GAU1 DNA-lncRNA triplex formation in tumorigenesis and providing a concept in the dynamics of isomerase assisted DNA-RNA hybridization.© 2024. The Author(s).