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The G2 DNA damage checkpoint: Could this ancient regulator be the Achilles heel of cancer?

2009; Taylor & Francis; Volume: 8; Issue: 15 Linguagem: Inglês

10.4161/cbt.8.15.9081

1555-8576

Karen M. Kuntz, Matthew J. O’Connell,

PARP inhibition in cancer therapy

AbstractThe maintenance of genomic integrity is important in normal cell growth and organism development, as well as in the prevention of cancer. Cell cycle checkpoints allow the cell time to complete replication and repair DNA damage before it can pass to the next cell cycle stage. These checkpoints ensure faithful segregation of one undamaged copy of the genome to each daughter cell. In humans, a DNA damage-based checkpoint signal in G1 is propagated through activation of the tumor suppressor p53, which is mutated in many cancers. Chk1, a serine/threonine kinase, controls checkpoint responses in G2. Chk1 is activated by the concerted action of many upstream proteins and prevents a cell from entering mitosis with damaged or incompletely replicated DNA. This checkpoint is conserved from the fission yeast, Schizosaccharomyces pombe through to humans. However, unlike p53, G2 checkpoint genes are rarely if ever mutated in cancer cells. This suggests that these genes are essential for tumor cell viability and may represent valid anti-cancer drug targets. This review will describe the current understanding of the G2 checkpoint including how the human biology has been informed by studies in fission yeast. It will also discuss the present status and future of potential cancer therapies aimed at inactivating this signaling pathway in tumor cells.Genetic studies regarding cell cycle progression in simple model organisms such as the yeasts have been extremely informative for understanding these processes in human cells – both in normal development, and in cancer. All eukaryotes share many of the controls over cell cycle progression, particularly those functioning at the transition from G2 into mitosis. However, human cells have acquired additional controls not present in the yeasts that act in G1 to coordinate extracellular signals with cell cycle progression, and to direct the alternative cell fates of senescence and apoptosis. Such controls are frequently mutated in tumor cells, and thus the resulting cancer cell cycle more closely resembles the more primitive controls in the yeasts. In both systems, studies of how cell cycle progression is influenced by genome integrity checkpoints has revealed a complex and highly conserved signaling cascade also functioning at the G2 to mitosis (G2/M) transition. This checkpoint may represent an "Achilles heel" by which the differences between somatic and tumor cell cycles may be exploited to selectively kill tumor cells.