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Updated: May 21, 2025

CRISPR/Cas9 Editing of the C. elegans rbm-3.2 Gene using the dpy-10 Co-CRISPR Screening Marker and Assembled Ribonucleoprotein Complexes.
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Published on: December 11, 2020

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Synthesis of an RBM39 Degrader That Downregulates CEP192 and Induces Disorganized Spindle Structures

Xilin Lyu1, Xiancheng Wang1,2, Dongze Lin3,4

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China.

Journal of Medicinal Chemistry
|March 19, 2025
PubMed

Insights

Depleting RNA-binding protein 39 (RBM39) causes cancer cell death by disrupting splicing and affecting CEP192. This research reveals RBM39 degraders as promising anticancer agents.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genomics

Background:

  • RNA-binding protein 39 (RBM39) is vital for mRNA splicing and integrity.
  • RBM39 depletion exhibits significant anticancer activity by inducing splicing defects.

Purpose of the Study:

  • To identify key downstream effectors of RBM39 depletion.
  • To compare the effects of two distinct RBM39-targeting compounds, CB039 and Indisulam.

Main Methods:

  • Multiomics approach including proteomics and RNA sequencing.
  • DepMap dependency assessment across 1,100 cancer cell lines.
  • Investigated CEP192 splicing and protein levels following compound treatment or RBM39 knockdown.

Main Results:

  • CEP192 was identified as a crucial gene, essential in 96% of analyzed cancer cell lines.
  • CB039 and Indisulam induced CEP192 exon 42 skipping and reduced CEP192 protein levels.
  • CEP192 knockdown or CB039 treatment caused spindle disorganization and failed chromosome segregation.

Conclusions:

  • RBM39 depletion disrupts CEP192 splicing and function, leading to mitotic defects.
  • Characterization of RBM39's downstream effects highlights the therapeutic potential of RBM39 degraders in cancer treatment.

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