8. G2/DNA Damage Checkpoint

 

8.1. G2/DNA Damage Checkpoint

 

In the case of DNA damage, in order to postpone the cell cycle advancement then cells trigger the checkpoint. This in turn, permits timely overhaul for DNA before becoming compelled to S-phase or mitosis (Calonge T M and O’Connell M J., 2008). 

                                                                                                             

There are many proteins that cooperate to promote Chk1 while G2 occurs. Chk1 ascertains that the mitotic cyclin–dependent kinase stays in an inhibitory mode, as in this scenario it is essential for ChK1 to maintain its role as an effector protein kinase (Calonge T M and O’Connell M J., 2008).

 

For occurrence of the existence in G2 despite DNA damage, then the renewal of cell cycle and entrance into mitosis must be permitted as the checkpoint is restricted (Calonge T M and O’Connell M J., 2008).

 

Furthermore, for maintaining the cell existence then two critical cellular responses will be induced as DNA damage is uncovered (Calonge T M and O’Connell M J., 2008)::

 

(i) To initiate repair at the sites where DNA are damaged then lesion-specific repair pathways become stimulated (Calonge T M and O’Connell M J., 2008). (ii) The process that results in postponement of the cell cycle advancement includes cyclin-dependent kinase (CDK), needing to be controlled in a negative way by cell cycle checkpoints. This, in turn, permits enough time for completion of the repair procedure to take place (Calonge T M and O’Connell M J., 2008).

 

It is also known that there are two main DNA damage checkpoints in eukaryotic cells (Calonge T M and O’Connell M J., 2008): (i) a p53-dependent retort, which facilitate transactivation of the Cdk2 inhibitor p21 in the higher organisms, and can cause obstruction to cell cycle advancement in G1 (Calonge T M and O’Connell M J., 2008). In addition p53, through PUMA and NOXA (pro-apoptotic genes}, can induce apoptosis as a response to DNA damage (Giono L E et al., 2006) (Calonge T M and O’Connell M J., 2008). (ii) In order to prevent the cells from entering mitosis and ascertain that the mitotic CDK, Cdc2 stays deactivated, it was discovered that there is a more conserved checkpoint, which spins out from yeast to human and is functional in S and G2 phase (Calonge T M and O’Connell M J., 2008). This checkpoint terminates when the ChK1 induction takes place. ChK1 is a protein kinase, which through the kinase Wee1 and phosphatase Cdc25 (a regulator Cdc2), controls the deactivation role of tyrosine phosphorylation on Cdc2 (ÓConnell M J et al., 2000 as cited in Calonge T M and O’Connell M J., 2008) (Calonge T M and O’Connell M J., 2008). However, when the overhaul is finished then there is a time for mitosis to transpire as a consequence of triggering Cdc2, which is responsible for cell survival (Calonge T M and O’Connell M J., 2008). 

 

G2/DNA Damage Checkpoint References

 

1.        Calonge, T. M. & O’Connell, M. J. Turning off the G2 DNA damage checkpoint. DNA Repair (Amst). 7, 136–140 (2008).

2.        Giono, L. E. & Manfredi, J. J. The p53 tumor suppressor participates in multiple cell cycle checkpoints. J. Cell. Physiol. 209, 13–20 (2006).

3.        O’Connell, M. J., Walworth, N. C. & Carr, A. M. The G2-phase DNA-damage checkpoint. Trends Cell Biol. 10, 296–303 (2000).

 

8.2. ChK1 Stimulation and Mechanism of Extinction of Chk1 Arbitrated Signal

 

It is known that the DNA damage initiates the Chk1 kinase functionality, which is related to ATM and ATR (PI3K protein kinases) phosphorylating the C-domain residues on Chk1 (Calonge T M and O’Connell M J., 2008).

 

There is a need for Chk1 inhibition to take place in order to terminate the checkpoint facilitated cell cycle arrest (Calonge T M and O’Connell M J., 2008).

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This process even in the absence of DNA overhaul, can induce the entrance into mitosis (Latif C et al., 2004) (Calonge T M and O’Connell M J., 2008).

 

There are three mechanisms associated with events related to extinction machinery of Chk1 (Calonge T M and O’Connell M J., 2008):

 

1. Protein phosphatases play a role in overturning and opposing the induction of ChK1 that happens thorough DNA damage activated phosphorylation.

2. Activation of phosphorylation is a marker for protein degradation and continuation in signaling is necessary for the checkpoint maintenance.

3. The cell cycle arrest promoted by checkpoint activation can be antagonized by other signaling pathways in order to trigger mitosis

 

ChK1 Stimulation and Mechanism of Extinction of Chk1 Arbitrated Signal References

 

1.        Calonge, T. M. & O’Connell, M. J. Turning off the G2 DNA damage checkpoint. DNA Repair (Amst). 7, 136–140 (2008).

2.        Latif, C., Elzen, N. R. den & O’Connell, M. J. DNA damage checkpoint maintenance through sustained Chk1 activity. J. Cell Sci. 117, 3489–3498 (2004).