Mammalian G1 and G2 phase checkpoints.
This present review explores the mechanisms for DNA damage induced G1 and G2 arrest in mammalian cells. The complexity of the TP53 pathway is attested to by the variety of genes regulated by TP53, many of which require further investigation to bring their importance into focus. One gene intensely studied, p21, has been linked to the G1 arrest mechanism and may, like TP53, be involved in some aspect of DNA repair. The outcome of TP53 activation for cell survival is equally complex and relies much upon cellular context and the type of DNA damaging agent employed. Although TP53 may participate in sensing DNA damage, additional components are likely to be required. Much of the focus on defining the mechanism of G2 arrest in mammalian cells has concentrated on the cyclin B1/CDC2 kinase. Activation of this kinase is suppressed by DNA damage, and this may result from the imposition of inhibitory phosphorylations on the CDC2 kinase as well as downregulation of cyclin B1 levels. The logical point where the G2 checkpoint interacts with the CDC2-CDC25C autocatalytic loop to prevent CDC2 activation remains to be defined and could involve inhibition of CDC25C-CDC2 interaction. It is hoped that moving upstream of CDC2 towards the point where DNA damage is sensed by the cell will uncover homologues of yeast components implicated in G2 checkpoint control. The finding that certain G2 checkpoint abrogators preferentially synergize with DNA damaging agents in cells with defective TP53 provides a potential pharmacological route through which TP53 defective cells might be targeted for destruction. Further exploration of this vulnerability might prove useful for future anti-cancer drug discovery efforts.
O'Connor
P M
PM
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D016195:G2 Phase / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D016158:Genes, p53 / Q000235:genetics*; D008322:Mammals; D010766:Phosphorylation; D012175:Retinoblastoma / Q000737:chemistry / Q000503:physiopathology
D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases