MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Genome Res. 2022 Jun;32(6):1026-1041. doi: 10.1101/gr.275831.121. Epub 2022 May 24.
Polypeptides encoded by long noncoding RNAs (lncRNAs) are a novel class of functional molecules. However, whether these hidden polypeptides participate in the TP53 pathway and play a significant biological role is still unclear. Here, we discover that TP53-regulated lncRNAs can encode peptides, two of which are functional in various human cell lines. Using ribosome profiling and RNA-seq approaches in HepG2 cells, we systematically identified more than 300 novel TP53-regulated lncRNAs and further confirmed that 15 of these TP53-regulated lncRNAs encode peptides. Furthermore, several peptides were validated by mass spectrometry. Ten of the novel translational lncRNAs are directly inducible by TP53 in response to DNA damage. We show that the TP53-inducible peptides TP53LC02 and TP53LC04, but not their lncRNAs, can suppress cell proliferation. TP53LC04 peptide also has a function associated with cell proliferation by regulating the cell cycle in response to DNA damage. This study shows that TP53-regulated lncRNAs can encode new functional peptides, leading to the expansion of the TP53 tumor-suppressor network and providing novel potential targets for cancer therapy.
长非编码 RNA（lncRNA）编码的多肽是一类新的功能分子。然而，这些隐藏的多肽是否参与 TP53 途径并发挥重要的生物学作用尚不清楚。在这里，我们发现 TP53 调控的 lncRNA 可以编码肽，其中两种在各种人类细胞系中具有功能。我们使用 HepG2 细胞中的核糖体图谱和 RNA-seq 方法，系统地鉴定了超过 300 个新的 TP53 调控的 lncRNA，并进一步证实其中 15 个 TP53 调控的 lncRNA 编码肽。此外，通过质谱验证了几种肽。在 DNA 损伤的情况下，10 个新的翻译性 lncRNA 可被 TP53 直接诱导。我们表明，TP53 诱导的肽 TP53LC02 和 TP53LC04，但不是它们的 lncRNA，可以抑制细胞增殖。TP53LC04 肽还可以通过调节细胞周期来响应 DNA 损伤，从而发挥与细胞增殖相关的功能。这项研究表明，TP53 调控的 lncRNA 可以编码新的功能肽，从而扩展了 TP53 肿瘤抑制网络，并为癌症治疗提供了新的潜在靶点。
