G2-M DNA damage checkpoint

[1] The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

[4] Many proteins involved in this positive feedback loop drive the activation of the CyclinB-Cdc2 complex because entry into mitosis requires an all-or-none response.

[5] Through experiments in Xenopus laevis cell-free egg extracts, such model was confirmed as the basis for entry into mitosis.

[6] Proteins that localize to sites of DNA damage in the G2 phase initiate a signaling cascade that regulates important components of the pathway, as described above, therefore controlling mitotic entry via CyclinB-Cdc2 activity.

[1] Inefficient repair of DNA damaged by ionizing radiation or chemical agents in these mutants revealed proteins essential in this pathway.

Early signaling proteins in the checkpoint pathway are members of a family of phosphatidylinositol 3-kinases, rad3 in yeast and ATR in vertebrates, that are believed to localize to sites of DNA damage.

[9] Chk1 is an effector protein kinase that maintains mitotic cyclin in an inactive state and is phosphorylated by rad3 between S phase and mitosis, implicating its specific role in G2 arrest.

[11] In addition, overexpression of Chk1 rescues the radiation sensitivity of rad mutants, presumably by allowing DNA repair to take place before entry into mitosis.

[13][15] Multiple pathways are involved in the checkpoint response and thus, the targeting of Cdc25 is not the sole mechanism underlying cell cycle delay, as some models have proposed.

Its necessity is demonstrated by the fact that in the absence of rad18, DNA is unable to be repaired even when G2 arrest is prolonged by other means.

[17] The absence of p21 or 14-3-3 cannot sufficiently inhibit the CyclinB-Cdc2 complex, thus exhibiting the regulatory control of p53 and p21 in the G2 checkpoint in response to DNA damage.

[11] Inactivation of Chk1 is sufficient to surpass the checkpoint and promote entry into mitosis, regardless if DNA damage is repaired.

More specifically, they have been implicated in being involved in the G2/M transition by localizing to the centrosome, which thus leads to studies in manipulating such proteins in order to improve cancer's sensitivity to radiation and chemotherapy.

[13] Chk1 has important implications in drug targeting for cancer as its function acts in response to DNA damage.