DNA damage checkpoints

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. 

In contrast to the DNA damage checkpoint, the mitotic spindle checkpoint is essential for cell viability. Dierefore, targeting kinases of the spindle checkpoint including Bubl, BubRl, and Mpsl might be a valid strategy for anticancer treatment. 

In addition to their inherent self-sustaining properties, brain tumor stem cells may be more resistant to chemotherapy and radiation therapy than other tumor cells. Bao et al. (2006) found glioma stem cells (CD133+) were relatively radioresistant compared to CD133- tumor cells and preferentially activated the DNA damage checkpoint response. This relative resistance to standard treatment approaches of tumor stem cells compared to the majority of other cells within a tumor may underlie our current inability to cure patients with aggressive brain tumors such as glioblastoma. 

Sanchez Y, Bachant J, Wang H et al 1999 Control of the DNA damage checkpoint by chkl and rad53 protein kinases through distinct mechanisms. Science 286 1166-1171... 

Reconstitution of a DNA damage checkpoint in extracts derivedfrom Xenopus eggs... 

Keogh MC, Kim JA, Downey M, Fillingham J, Chowdhury D, Harrison JC, Onishi M, Datta N, Galicia S, Emili A et al (2006) A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery. Nature 439 497-501... 

Boisvert, F.M., Dery U., Masson, J.Y. and Richard, S. (2005) Arginine methylation of MREll by PRMTl is required for DNA damage checkpoint control. Genes and Development, 19, 671-676. 

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. 

If DNA damage is present, DNA replication can be stopped (DNA damage checkpoint)... 

The cell cycle contains built-in control mechanisms that register defects in the course of the cell cycle and bring about a halt in the cell cycle to enable the fault to be repaired or to lead the cell to programmed cell death. These control mechanisms are also known as checkpoints. These are biochemical pathways that are activated when a fault occurs and can influence other critical steps of the cell cycle. Of particular importance for the cell cycle is the DNA damage checkpoint. Another important checkpoint is the spindle assembly checkpoint, which is not well biochemically characterized, however. 

The signaling pathways that lead from the appearance of DNA damage to a halt in the cell cycle include a number of components of which the function has only partially been characterized. So far, it has been estabhshed that the DNA damage checkpoints of different organisms have a common homologous component, namely a protein kinase, which belongs to the superfamUy of P13-kinases (see 6.6). 

A cell that has suffered DNA damage can bring about a halt in the cell cycle with the help of intrinsic control mechanisms (DNA damage checkpoints, see 13.7). The aim is... 

The p53 protein has been identified as a component of the DNA damage checkpoint in animals and humans, from which it is assumed to be homologous to the DNA damage checkpoint in the yeast S. cerevisiae (see 13.7). 

Checking for completion of replication and for DNA damage. The first checkpoint in the cell cycle is the start or Gj 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... 

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