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A Molecular Glue of RBM39 and DCAF15 Arrests Cell Cycle Progression by Downregulation of CEP192

ABSTRACT: RBM39 is a crucial component of the spliceosome that is critical for the integrity of mature mRNA, while depletion of RBM39 by Indisulam significantly increases RNA splicing defects. The antitumor activity of Indisulam is partially attributed to its inhibitory effects on cell cycle progression. To identify the key effector proteins responsible for cell cycle arrest following RBM39 depletion, we employed a multi-omics approach utilizing two chemotypes of RBM39 degraders: Indisulam and CB039. Through proteomics analysis, RNA sequencing, and DepMap cancer cell line dependency analysis, we identified CEP192 as a key gene that exhibited dependency in 96% of 1,100 cancer cell lines. In a panel of eight cancer cell lines, we observed consistent phenotypes upon treatment with CB039 and Indisulam, including skipping of CEP192 exon 42 and downregulation of the CEP192 protein. Mechanistically, treatment with CB039 and Indisulam, as well as CEP192 knockdown via RNA interference, resulted in arrest of cell cycle progression at the G2/M phase. This treatment also induced a disorganized spindle phenotype, as well as condensed and undivided chromosomes. In summary, this work enhances our understanding of the anti-mitotic mechanism underlying RBM39 molecular glue degraders.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Colon Cancer

SUBMITTER: He Huang

LAB HEAD: He Huang

PROVIDER: PXD056341 | Pride | 2025-03-20

REPOSITORIES: Pride

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