Bieging-Rolett Kathryn T, Kaiser Alyssa M, Morgens David W, Boutelle Anthony M, Seoane Jose A, Van Nostrand Eric L, Zhu Changyu, Houlihan Shauna L, Mello Stephano S, Yee Brian A, McClendon Jacob, Pierce Sarah E, Winters Ian P, Wang Mengxiong, Connolly Andrew J, Lowe Scott W, Curtis Christina, Yeo Gene W, Winslow Monte M, Bassik Michael C, Attardi Laura D
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Mol Cell. 2020 Nov 5;80(3):452-469.e9. doi: 10.1016/j.molcel.2020.10.022.
Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood. Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR-Cas9-based genetic screens in vivo. These screens converge upon the p53-inducible gene Zmat3, encoding an RNA-binding protein, and we demonstrate that ZMAT3 is an important tumor suppressor downstream of p53 in mouse Kras-driven lung and liver cancers and human carcinomas. Integrative analysis of the ZMAT3 RNA-binding landscape and transcriptomic profiling reveals that ZMAT3 directly modulates exon inclusion in transcripts encoding proteins of diverse functions, including the p53 inhibitors MDM4 and MDM2, splicing regulators, and components of varied cellular processes. Interestingly, these exons are enriched in NMD signals, and, accordingly, ZMAT3 broadly affects target transcript stability. Collectively, these studies reveal ZMAT3 as a novel RNA-splicing and homeostasis regulator and a key component of p53-mediated tumor suppression.
尽管TP53是人类癌症中最常发生突变的基因，但介导肿瘤抑制的p53依赖性转录程序仍未完全被理解。在此，为了揭示p53下游在肿瘤抑制中的关键成分，我们在体内进行了基于无偏向RNAi和CRISPR-Cas9的基因筛选。这些筛选聚焦于p53诱导基因Zmat3，其编码一种RNA结合蛋白，并且我们证明ZMAT3是小鼠Kras驱动的肺癌和肝癌以及人类癌症中p53下游的一种重要肿瘤抑制因子。对ZMAT3 RNA结合图谱和转录组分析的综合分析揭示，ZMAT3直接调节编码多种功能蛋白的转录本中的外显子包含，这些功能包括p53抑制剂MDM4和MDM2、剪接调节因子以及各种细胞过程的成分。有趣的是，这些外显子富含NMD信号，因此，ZMAT3广泛影响靶转录本的稳定性。总的来说，这些研究揭示ZMAT3是一种新型的RNA剪接和稳态调节因子以及p53介导的肿瘤抑制的关键成分。
