Cell Cycle Control: G2/M DNA Damage Checkpoint

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Pathway Description:

The G2/M DNA damage checkpoint serves to prevent the cell from entering mitosis (M-phase) with genomic DNA damage. Specifically, the activity of the cdc2-Cyclin B complex is pivotal in regulating the G2-phase transition wherein cdc2 is maintained in an inactive state by the tyrosine kinases Wee1 and Myt1. It is thought that coordinated action of the kinase Aurora A and the cofactor Bora activate PLK1 as cells approach the M-phase, which in turn activates the phosphatase cdc25 and downstream cdc2 activity, establishing a feedback amplification loop that efficiently drives the cell into mitosis. Importantly, DNA damage cues activate the sensory DNA-PK/ATM/ATR kinases, which relay two parallel cascades that ultimately serve to inactivate the cdc2-Cyclin B complex. The first cascade rapidly inhibits progression into mitosis: the Chk kinases phosphorylate and inactivate cdc25, which then prevents activation of cdc2. The slower second parallel cascade involves phosphorylation of p53 and allows for its dissociation from MDM2 and MDM4, which activates DNA binding and transcriptional regulatory activity, respectively. The transcriptional ability of p53 is further augmented through acetylation by p300/PCAF. The second cascade constitutes the p53 downstream regulated genes including: 14-3-3, which binds to the phosphorylated cdc2-Cyclin B complex and exports it from the nucleus; GADD45, which binds to and dissociates the cdc2-Cyclin B complex; and p21 Cip1, an inhibitor of a subset of the cyclin-dependent kinases including cdc2. In human cancer, p53 is commonly mutated indicating that this checkpoint is a critical barrier to tumor formation. In addition, sporadic as well as familial mutations in the DNA-repair proteins such as the BRCA-family, ATM and the Fanconi Anemia proteins further highlight this key tumor suppressor checkpoint.

Selected Reviews:

• Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer 9(6), 400–14.
• Boutros R, Lobjois V, Ducommun B (2007) CDC25 phosphatases in cancer cells: key players? Good targets? Nat. Rev. Cancer 7(7), 495–507.
• Junttila MR, Evan GI (2009) p53--a Jack of all trades but master of none. Nat. Rev. Cancer 9(11), 821–9.
• Lindqvist A, Rodríguez-Bravo V, Medema RH (2009) The decision to enter mitosis: feedback and redundancy in the mitotic entry network. J. Cell Biol. 185(2), 193–202.
• Meek DW (2009) Tumour suppression by p53: a role for the DNA damage response? Nat. Rev. Cancer 9(10), 714–23.
• Moldovan GL, D'Andrea AD (2009) How the fanconi anemia pathway guards the genome. Annu. Rev. Genet. 43, 223–49.
• Reinhardt HC, Yaffe MB (2009) Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Curr. Opin. Cell Biol. 21(2), 245–55.

We would like to thank Dr. Hans Widlund, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, for contributing to this diagram.