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Publication

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

Molecular cell | 2020

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.

Pubmed ID: 33157015 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: T32 CA009302
Agency: NCI NIH HHS, United States
Id: F32 CA162681
Agency: NCI NIH HHS, United States
Id: P30 CA008748
Agency: NCI NIH HHS, United States
Id: P01 CA087497
Agency: NCI NIH HHS, United States
Id: P30 CA023100
Agency: NCI NIH HHS, United States
Id: R01 CA233944
Agency: NCI NIH HHS, United States
Id: R35 CA197591

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Multivariate Analysis of Transcript Splicing (tool)

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Software tool to detect differential alternative splicing events from RNA-Seq data. Calculates P value and false discovery rate that difference in isoform ratio of gene between two conditions exceeds given user defined threshold. Can automatically detect and analyze alternative splicing events corresponding to all major types of alternative splicing patterns. Handles replicate RNA-Seq data from both paired and unpaired study design.

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DESeq2 (tool)

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Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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