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^G12D-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是人类癌症中最常见的突变基因，但介导肿瘤抑制的 p53 依赖性转录程序仍不完全清楚。在这里，为了揭示 p53 下游在肿瘤抑制中的关键成分，我们在体内进行了无偏 RNAi 和基于 CRISPR-Cas9 的遗传筛选。这些筛选集中在 p53 诱导基因Zmat3上，该基因编码 RNA 结合蛋白，我们证明 ZMAT3 是小鼠Kras ^{G12D中 p53 下游的重要肿瘤抑制因子}-驱动肺癌、肝癌和人类癌症。对 ZMAT3 RNA 结合景观和转录组分析的综合分析表明，ZMAT3 直接调节编码多种功能蛋白的转录物中的外显子包含，包括 p53 抑制剂 MDM4 和 MDM2、剪接调节因子以及各种细胞过程的组件。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，这些研究表明 ZMAT3 是一种新型 RNA 剪接和稳态调节剂，也是 p53 介导的肿瘤抑制的关键组成部分。