Differences in integration of the mammalian cell cycle: Implications for cell survival and genomic stability

The proper temporal order of cell cycle events is maintained by feedback control mechanisms called checkpoints. Different mammalian cell lines have different numbers and types of checkpoints. In general, cell lines can be classified as having either stringent or relaxed cell cycle control based upon their response to agents that perturb specific cell cycle events. In the presence of agents that disrupt assembly of the mitotic spindle apparatus, cell types with stringent cell cycle control arrest cell cycle progression in mitosis, whereas cells with relaxed cell cycle control rapidly progress out of mitosis and into subsequent cell cycles. In response to inhibition of DNA synthesis, cell types with stringent cell cycle control down-regulate protein synthesis, cell cycle regulatory protein accumulation and cell growth. In contrast, cell types with relaxed cell cycle control aberrantly accumulate cell cycle regulatory proteins to supramitotic levels during the period of DNA synthesis inhibition, and grow to exceed the normal size at mitosis. Thus, cells with stringent cell cycle control have checkpoint mechanisms that serve to arrest cell cycle progression in response to disruption of the mitotic spindle and inhibition of DNA synthesis. Almost all human cell lines display stringent cell cycle control, whereas rodent cell lines generally have relaxed cell cycle control.;The cytotoxicity that results from a transient inhibition of cell cycle events is not due to the biochemical action of the treatment modality per se, but rather derives from the dissociation of normally coupled cell cycle events. In the case of treatment modalities that transiently inhibit DNA synthesis, the aberrant accumulation of cell cycle regulatory proteins during the period of inhibition is a primary determinant of subsequent cytotoxicity.;Cell types with relaxed cell cycle control also have an increased propensity for gene amplification and neoplastic transformation. These findings are consistent with the concept that cell cycle checkpoints are critical for the maintenance of genomic integrity and the loss of checkpoints may result in increased genomic instability and an accumulation of genetic changes that contributes to the development and progression of cancer.