Reid2016

A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells

• Reid at al, 2016 Genetics; 204:807–819

CKS1B, a conserved component of CDK, is amplified in multiple cancers and its involvement in multiple cell cycle processes suggests a role in oncogenesis. However, the consequences of increased CKS1B expression are unclear, due to both positive and negative effects of CKS1 on cell cycle progression (Dunphy and Newport 1989; Patra and Dunphy 1996; Patra et al. 1999). Our systematic genetic approach in yeast defines the consequence of CKS1 expression by identifying mutations that fail to tolerate increased expression of CKS1. The genetic screen identified a number of mutations that affect cell cycle progression in G2 and M cell cycle phases, but particularly identified genes affecting the transitions between G2–M (mitotic entry) and M–G1 (mitotic exit). Subsequent genetic analyses show that these SDL interactions depend on the activity of two important CDK inhibitors, Swe1 and Sic1.

Mutual exclusion analysis revealed that the human homolog of Cdc5, PLK1, is rarely down-regulated when CKS1B is overexpressed. Furthermore, multiple experiments show that human cells with increased CKS1B expression exhibit decreased growth and increased apoptosis upon PLK1 inhibition by either shRNA or with the specific PLK1 inhibitor Volasertib (Figure 3, Figure 4, Figure S5, Figure S6, and Figure S7). Thus, despite the evolutionary distance between yeast and humans, the SDL interaction we identified in yeast is conserved in humans.

We curate here just this one synthetic lethal interaction between PLK1 NCBI Gene id 5347 and CKS1B NCBI Gene id 1163 because this is the only interaction sufficiently characterized in human cells.