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

Kathryn T Bieging-Rolett1, Alyssa M Kaiser1, David W Morgens2

  • 1Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Molecular Cell
|November 6, 2020
PubMed

Insights

Researchers identified Zmat3 (ZMAT3) as a crucial tumor suppressor gene downstream of TP53. ZMAT3 regulates RNA splicing and stability, impacting cancer cell growth and survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • TP53 is frequently mutated in human cancers, but its tumor-suppressive transcriptional targets are not fully understood.
  • Identifying downstream effectors of p53 is critical for understanding cancer development and for developing targeted therapies.

Purpose of the Study:

  • To uncover novel downstream targets of p53 involved in tumor suppression.
  • To investigate the role of the p53-inducible gene Zmat3 (ZMAT3) in cancer.

Main Methods:

  • Unbiased in vivo RNAi and CRISPR-Cas9 genetic screens were employed.
  • Integrative analysis of ZMAT3's RNA-binding landscape and transcriptomic profiling was performed.

Main Results:

  • Screens identified ZMAT3 as a key downstream effector of p53.
  • ZMAT3 functions as a tumor suppressor in Kras-driven mouse lung/liver cancers and human carcinomas.
  • ZMAT3 directly modulates exon inclusion, affecting transcripts of p53 inhibitors (MDM2, MDM4) and splicing regulators.
  • ZMAT3 influences target transcript stability, particularly those with NMD signals.

Conclusions:

  • ZMAT3 is a novel regulator of RNA splicing and homeostasis.
  • ZMAT3 is a critical component of p53-mediated tumor suppression, offering potential therapeutic targets.
Keywords:
CRISPR screenMdm4RBPRNAi screenZmat3alternative splicinghepatocellular carcinomalung adenocarcinomap53tumor suppression

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