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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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RPL22 is a tumor suppressor in MSI-high cancers and a splicing regulator of MDM4

Hannah N W Weinstein1, Kevin Hu1, Lisa Fish2

  • 1Division of Hematology/Oncology, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, Bakar Computational Health Sciences Institute, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

Cell Reports
|August 15, 2024
PubMed

Insights

Microsatellite instability-high (MSI-H) tumors with RPL22 mutations show altered MDM4 splicing. This impacts cell proliferation and drug resistance, revealing a common splicing circuit for potential therapeutic targeting.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Microsatellite instability-high (MSI-H) tumors often present with a high mutation rate but intact TP53.
  • Frameshift mutations in RPL22, a ribosomal protein, are common in MSI-H tumors.

Purpose of the Study:

  • To investigate the role of RPL22 in modulating MDM4 splicing.
  • To understand the functional consequences of RPL22 mutations in MSI-H tumors.
  • To identify potential therapeutic targets within the MDM4-p53 axis.

Main Methods:

  • Investigated RPL22's role in alternative splicing of MDM4.
  • Analyzed the effect of RPL22 loss on cell proliferation and drug resistance.
  • Examined RPL22's regulation of its paralog, RPL22L1.

Main Results:

  • RPL22 loss promotes MDM4 exon 6 inclusion, increasing cell proliferation.
  • RPL22 deficiency enhances resistance to MDM inhibitors like Nutlin-3a.
  • RPL22 represses RPL22L1 expression via cryptic exon splicing, leading to truncated transcripts.

Conclusions:

  • RPL22 mutations disrupt MDM4 splicing, contributing to oncogenesis in MSI-H tumors.
  • A common splicing circuit involving RPL22, MDM4, and RPL22L1 is identified in MSI-H tumors.
  • Targeting the MDM4-p53 axis and RPL22L1 induction presents a potential therapeutic strategy.
Keywords:
CP: CancerCP: Molecular biologyMDM4MDM4 exon 6 inclusionMSI-HRPL22RPL22 p.K15fsalternative splicingmicrosattelite instability-highp53ribosomal proteinstumor suppressor

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