The essentiality landscape of cell cycle-related genes in human pluripotent and cancer cells

Cell cycle regulation is a complex system consisting of growth-promoting and growth-restricting mechanisms, whose coordinated activity is vital for proper division and propagation. Alterations in this regulation may lead to uncontrolled proliferation and genomic instability, triggering carcinogenesis. Here, we conducted a comprehensive bioinformatic analysis of cell cycle-related genes using data from CRISPR/Cas9 loss-of-function screens performed in four cancer cell lines and human embryonic stem cells (hESCs). Our results indicate that cell cycle genes, and in particular S phase and checkpoint genes, are highly essential for the growth of cancer and pluripotent cells. However, checkpoint genes are found to underlie the differences between the cell cycle features of these cell types. Interestingly, while growth-promoting cell cycle genes overlap considerably between cancer and stem cells, growth-restricting cell cycle genes are completely distinct. Moreover, growth-restricting genes are consistently less frequent in cancer cells than in hESCs. Here we show that most of these genes are regulated by the tumor suppressor gene TP53, which is mutated in most cancer cells, and therefore the growth-restriction system in cancer lacks important factors and does not function properly. Intriguingly, M phase genes are specifically essential for the growth of hESCs and are highly abundant among hESC-enriched genes, suggesting a unique M phase circuitry in pluripotent cells. These results emphasize the importance of conducting cell cycle studies in cells with intact genomes and not in cancer cells, in order to obtain an authentic representation of the genetic features of the cell cycle.