DNA replication checkpoint

Whether the DNA replication checkpoint directly affects the Plxl activation pathway for Cdc25C has not yet been established. It is possible that the replication checkpoint arrests the cell cycle prior to initiation of the Plxl kinase cascade. Further characterization of upstream components of the cascade should reveal whether it is directly regulated by replication checkpoint activation. Such a characterization will also have importance for other M phase events, inasmuch as Plxl also regulates bipolar spindle formation, APC activation and cytokinesis (Qian et al 1998, 1999). These multiple functions of Plxl are associated with changes in localization of Plxl, and are most likely mediated by protein—protein interaction with the polo box motif in the non-catalytic C-terminal half of Plxl. 

Eehner The spindle checkpoint works well and the DNA replication checkpoint is compromised but present in early Drosophila embryos. In addition, Sullivan has proposed that there is a back-up checkpoint mechanism during the syncytial stages (Fogarty et al 1997). If nuclei continue to go through the cell cycle in the presence of unreplicated DNA, they get disposed. The nuclei lose the connection with the centrosome, they fall into the interior of the egg and fail to become cellularized. 

The activity of CDC25 phosphatase is also central to the DNA damage and DNA replication checkpoints of the cell cycle. Upon activation of these checkpoints by DNA damage or the presence of unreplicated DNA, the CDC25 phosphatase is inactivated... 

Hekmat-Nejad M, You Z, Yee MC, Newport JW, Cimprich KA. Xenopus ATR is a replication-dependent chromatin-binding protein required for the DNA replication checkpoint. Curr. Biol. 2000 10 1565-1573. 

Kumagai A, Dunphy WG. Claspin, a novel protein required for the 27. activation of Chkl during a DNA replication checkpoint response... 

You Z, Kong L, Newport J. The role of single-stranded DNA and polymerase alpha in establishing the ATR, Hus 1 DNA replication checkpoint. J. Biol. Chem. 2002 277(30) 27088-27093. 

Michael WM, Ott R, Fanning E, Newport J. Activation of the DNA replication checkpoint through RNA synthesis by primase. Science 2000 289(5487) 2133-2137. 

Mailer In some cases I think it is a matter of thresholds. If you add enough DNA to an egg extract, you have a signal sent and heard. If it is a DN A-based signal, you need a certain amount of DNA to send the signal. The amount of DNA required is different for each checkpoint. Only 4N of irradiated DNA (4 nuclei///l) is sufficient for inducing apoptosis at the MBT. Andrew Murray showed that the spindle checkpoint requires a much higher amount of DNA (10000 nuclei///l) in the system to respond to nocodazole than does the replication checkpoint with aphidicolin (1000 nuclei//rl). 

Van Holde KE, Zlatanova J, Arents G, Moudrianakis E (1995) Chromatin structure and gene expression (Elign SCR, ed). Oxford University Press, Oxford, ppl-26 Wang Y, Beerman TA, Kowalski D (2001) Antitumor drug adozelesin differentially affects active and silent origins of DNA replication in yeast checkpoint kinase mutants. Cancer Res 61(9) 3787-3794... 

The cell cycle is a key process that recurs in a periodic manner. Early cell cycles in amphibian embryos are driven by a mitotic oscillator. This oscillator produces the repetitive activation of the cyclin-dependent kinase cdkl, also known as cdc2 [131]. Cyclin synthesis is sufficient to drive repetitive cell division cycles in amphibian embryonic cells [132]. The period of these relatively simple cell cycles is of the order of 30 min. In somatic cells the cell cycle becomes longer, with durations of up to 24 h or more, owing to the presence of checkpoints that ensure that a cell cycle phase is properly completed before the cell progresses to the next phase. The cell cycle goes successively through the phases Gl, S (DNA replication), G2, and M (mitosis) before a new cycle starts in Gl. After mitosis cells can also enter a quiescent phase GO, from which they enter Gl under mitogenic stimulation. 

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

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

Of the four phases, the two critical ones are DNA replication, which occurs during Gi to S phase, and the physical process of cell division, which occurs during G2 to M (for mitosis) phase these are critical checkpoints . 

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