A hallmark of the human cell cycle in normal somatic cell...

A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation (reviewed in Shackelford et al. 1999, Panagopoulos and Altmeyer 2021, Tyson and Novak 2022).

Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs (reviewed in Poon 2016).

Depending on the stage of the cell cycle that they regulate, the cell cycle checkpoints are divided into G1/S checkpoints, S phase checkpoints, G2/M checkpoints, and M/G1 checkpoints (reviewed in Poon 2016). Reactome currently has partial coverage of G1/S checkpoints (pathway G1/S DNA Damage Checkpoints), G2/M checkpoints (pathway G2/M Checkpoints), and M/G1 checkpoints (pathway Mitotic Spindle Checkpoint).

The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the TP53 (p53) tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear (reviewed in Golubnitschaja 2007, Groelly et al. 2023).