Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program

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 KrasG12D-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. [Display omitted] •RNAi and CRISPR screens in vivo reveal p53 targets with tumor suppressor activity•Zmat3 is a tumor suppressor in mouse lung and liver cancers and human carcinomas•Zmat3 binds RNA with unique positional specificity to regulate RNA splicing•Zmat3 RNA splicing affects transcripts involved in a variety of cellular processes p53 is a critically important but incompletely understood tumor suppressor. Bieging-Rolett et al. identify the p53 target gene Zmat3, encoding an RNA-binding protein, as a key tumor suppressor downstream of p53 in a broad range of cancers and uncover a role for ZMAT3 in regulating alternative RNA splicing.