Effect of CDK11 inhibition via OTS964 treatment on gene expression to assess implication on cellular processes including intron retention.

CDK11 has known to have functions in the cell cycle and RNA processing. It has been previously shown that, a mutation within CDK11 (G579S) confers resistance to CDK11 inhibition. To further understand the role of CDK11 in cancer, we performed RNA-sequencing in four cancer cell lines (A375, Cal51, DLD1 and MDA-MB-231 cells) in both wild-type and G579S background. Here, we report that treatment with CDK11 inhibitor OTS964 results in a notable increase in intron retention. The expression of CDK11-G579S rescues the abberent splicing in the presence of CDK11 inhibitior, OTS964. GSEA analysis of the transcripts with retained introns have roles in gene expression, splicing and cell cycle progression. In addition to splicing related genes, we also revealed that CDK11 inhibition results in a significant downregulaiton of genes associated with DNA repair. This was an on-target effect of OTS964 treatment as this downregulation was not observed in cells expressing CDK11-G579S. This data shows that CDK11 has improtant roles in RNA splicing and DNA damage repair pathways.