A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression.,Cell Death and Differentiation

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A novel long noncoding RNA Linc-ASEN represses cellular senescence through multileveled reduction of p21 expression.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41418-019-0467-6
Hyung Chul Lee ₁ , Donghee Kang ₁ , Namshik Han ₂ , Yerim Lee ₁ , Hyun Jung Hwang ₁ , Sat-Byol Lee ₃ , Jueng Soo You ₄ , Byung Soh Min ₃ , Heon Joo Park ₅ , Young-Gyu Ko ₆ , Myriam Gorospe ₇ , Jae-Seon Lee ₁

Affiliation

Long noncoding RNAs (lncRNAs) regulating diverse cellular processes implicate in many diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we identify a novel long intergenic noncoding RNA Linc-ASEN expresses in prematurely senescent cells. We find that Linc-ASEN associates with UPF1 by RNA pulldown mass spectrometry analysis, and represses cellular senescence by reducing p21 production transcriptionally and posttranscriptionally. Mechanistically, the Linc-ASEN-UPF1 complex suppressed p21 transcription by recruiting Polycomb Repressive Complex 1 (PRC1) and PRC2 to the p21 locus, and thereby preventing binding of the transcriptional activator p53 on the p21 promoter through histone modification. In addition, the Linc-ASEN-UPF1 complex repressed p21 expression posttranscriptionally by enhancing p21 mRNA decay in association with DCP1A. Accordingly, Linc-ASEN levels were found to correlate inversely with p21 mRNA levels in tumors from patient-derived mouse xenograft, in various human cancer tissues, and in aged mice tissues. Our results reveal that Linc-ASEN prevents cellular senescence by reducing the transcription and stability of p21 mRNA in concert with UPF1, and suggest that Linc-ASEN might be a potential therapeutic target in processes influenced by senescence, including cancer.

中文翻译：

一种新型长非编码 RNA Linc-ASEN 通过多水平减少 p21 表达来抑制细胞衰老。

长非编码 RNA (lncRNA) 调节多种细胞过程，与许多疾病有关。然而，lncRNA 在细胞衰老中的功能仍然很大程度上未知。在这里，我们鉴定了一种在过早衰老细胞中表达的新型长基因间非编码 RNA Linc-ASEN。我们通过 RNA Pulldown 质谱分析发现 Linc-ASEN 与 UPF1 结合，并通过转录和转录后减少 p21 的产生来抑制细胞衰老。从机制上讲，Linc-ASEN-UPF1 复合物通过将 Polycomb 抑制复合物 1 (PRC1) 和 PRC2 募集到 p21 位点来抑制 p21 转录，从而通过组蛋白修饰阻止转录激活因子 p53 与 p21 启动子结合。此外，Linc-ASEN-UPF1 复合物通过增强与 DCP1A 相关的 p21 mRNA 衰减来抑制 p21 转录后表达。因此，发现 Linc-ASEN 水平与来自患者的小鼠异种移植肿瘤、各种人类癌症组织和老年小鼠组织中的 p21 mRNA 水平呈负相关。我们的结果表明，Linc-ASEN 通过与 UPF1 协同降低 p21 mRNA 的转录和稳定性来预防细胞衰老，并表明 Linc-ASEN 可能是受衰老影响的过程（包括癌症）的潜在治疗靶点。

更新日期：2019-12-09

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