G2 DNA damage checkpoint

Hymenialdisins proved to be nanomolar inhibitors of G2 DNA damage checkpoint and of the protein kinases Chkl and Chk2 [56], mitogen-activated protein kinase 1 (MEK-1) [57], and of other kinases [58[ therefore, they could be valuable agents in cancer therapy. In addition, hymenialdisins have been show n to inhibit... 

Cell Cycle Control. Figure 3 The DNA damage checkpoint. In response to DNA damage cells activate p53 dependent and independent checkpoint pathways leading to cell cycle arrest at G1/S and G2/M allowing DNA repair. If the cellular damage cannot be repaired, cells can initiate apoptosis. 

Many of the control mechanisms of the cell cycle are of intrinsic nature and are constitutive, i.e., they are operational in every cell cycle and ensure the ordering of the individual steps. However, other control mechanisms exist that are not active in every cell cycle these are only induced when defects are detected in central cell cycle events. These control mechanisms are known as checkpoints. An example of a checkpoint that is only activated when required is the DNA damage checkpoint (see 13.7). This is a biochemical pathway that detects DNA damage and creates a signal that arrests cells in the Gl, S or G2 phase of the cell cycle. 

Other important cell cycle transitions are entry into S phase and the G2/M transition. At the G2/M transition, it is registered whether S phase has been completely executed, and the integrity of the DNA is examined at a DNA damage checkpoint. There are other important cell cycle transitions in M phase between metaphase and anaphase. At this point, an important and irreversible decision is made for progress of mitosis if the spindle apparatus is correctly formed and the sister chromatids are correctly aligned, the cell cycle may proceed. 

This protein has an important function in the G2/M DNA damage checkpoint. It serves to sequester the mitotic initiation complex, CDC2-cydin Bl, in the cyto-... 

Bijur, G.N., Briggs, B., Hitchcock, C.L., and Williams, M.V., Ascorbic acid-dehydroascorbate induces cell cycle arrest at G2/M DNA damage checkpoint during oxidative stress. Environ. 

Flow cytometric analyses demonstrated that pretreatment of Chinese hamster ovary cell line AS52 with 50 iM ascorbic acid before exposure to the hypoxanthine-xanthine oxidase radical generating system enhanced cell cycle arrest at the G2/M DNA damage checkpoint when compared to cells treated with hypoxanthine-xanthine oxidase without premedication (Bijur et al. 1999). Ascorbic acid had no effect on cell cycle progression in the absence of oxidative stress. 

Ouyang G, Yao L, Ruan K, Song G, Mao Y, Bao S (2009) Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways. Cell Biol Int 33 1237-1244... 

In contrast, UCN-01, a staurosporine derivative, acts as a potent inhibitor of the Chkl kinase and efficiently abrogates the G2 checkpoint upon DNA damage. Die forced entry into mitosis in the presence of DNA damage results in a mitotic form of apoptosis. Several clinical trials are currently exploring a combined treatment with UCN-01 and various DNA damaging diugs. In the same vein, inhibitors of Chk2 are developed and tested in clinical trials. 

Eernandez-Capetillo O, Allis CD, Nussenzweig A (2004) Phosphorylation of histone H2B at DNA double-strand breaks. J Exp Med 199(12) 1671—1677 Eernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A (2002) DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol 4(12) 993-997... 

Terrell J, Shih S, Dunn R, Hicke L (1998) A function for monoubiquitination in the internalization of a G protein-coupled receptor. Mol Cell 1 193-202 Tomoda K, Kubota Y, Kato J (1999) Degradation of the cydin-dependent-kinase inhibitor p27 is instigated by Jabl. Nature 398 160-165 Toyoshima F, Moriguchi T, Wada A, Fukuda M, Nishida, E (1998) Nudear export of cydin Bl and its possible role in the DNA damage-induced G2 checkpoint. EMBO J 17 2728-2735... 

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