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Mechanisms of G2 Phase Arrest in DNA Damage-Induced Checkpoint Response

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Checkpoint Controls and Targets in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

DNA damage activates cell cycle checkpoints and inhibits cell cycle progression. In G2 phase cells, the checkpoint response results in the inhibition of Cdc2/cyclin B activity, which, thereby, prevents G2/M transition, and, as a result, cells accumulate at the G2/M boundary. Both p53-depen-dent and -independent mechanisms are involved in the inhibition of Cdc2 kinase activity during the DNA damage-induced G2 phase checkpoint response. The p53-independent mechanism causes an acute but transient inhibition of the Cdc2/cyclin B activity through posttranslational modifications of the Cdc2-activating phosphatase Cdc25, whereas the p53-dependent mechanism causes a delayed but sustained inhibition of the Cdc2/cyclin B activity through both transactivation of p21, GADD45 and 14-3-3 and tran-srepression of Cdc2 and cyclin B. Because the p53-dependent mechanism is often defective in tumor cells, abrogation of the p53-independent mechanism to preferentially negate the G2 checkpoint response and induce programmed cell death in tumor cells has become an attractive adjuvant strategy in cancer therapy.

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  1. Department of Experimental Therapeutics, Division of Cancer Medicine, M. D. Anderson Cancer Center, Houston, TX, 77030, USA

    Jian Kuang & Ruoning Wang

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  1. Jian Kuang
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  1. M.D. Anderson Cancer Center, University of Texas, Holcombe Blvd. 1515, Houston, 77030, U.S.A.

    Zahid H. Siddik

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Kuang, J., Wang, R. (2010). Mechanisms of G2 Phase Arrest in DNA Damage-Induced Checkpoint Response. In: Siddik, Z. (eds) Checkpoint Controls and Targets in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-60761-178-3_3

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  • DOI: https://doi.org/10.1007/978-1-60761-178-3_3

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