The TP53 tumor suppressor is the most frequently mutated gene in human cancer. p53 suppresses tumorigenesis by transcriptionally regulating a network of target genes that play roles in various cellular processes. Though originally characterized as a critical regulator for responses to acute DNA damage (activation of apoptosis and cell cycle arrest), recent studies have highlighted new pathways and transcriptional targets downstream of p53 regulating genomic integrity, metabolism, redox biology, stemness, and non-cell autonomous signaling in tumor suppression. Here, we summarize our current understanding of p53-mediated tumor suppression, situating recent findings from mouse models and unbiased screens in the context of previous studies and arguing for the importance of the pleiotropic effects of the p53 transcriptional network in inhibiting cancer.

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.