G2M/DNA Damage Checkpoint

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 Cyclin B-cdc2 (CDK1) 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, hence 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 Cyclin B-cdc2 complex. The first cascade rapidly inhibits progression into mitosis: the Chk kinases phosphory- late and inactivate cdc25, which prevents activation of cdc2. The slower second parallel cascade involves phosphorylation of p53 and allows for its dissociation from MDM2 and MDM4 (MdmX), which activates DNA binding and transcriptional regulatory activity, respectively. The transcriptional ability of p53 is further augmented through acetylation by the co-activator complex p300/PCAF. The second cascade constitutes the p53 downstream-regulated genes including: 14-3-3, which binds to the phosphorylated Cyclin B-cdc2 complex and exports it from the nucleus; GADD45, which binds to and dissociates the Cyclin B-cdc2 complex; and p21 Cip1, an inhibitor of a subset of the cyclin-dependent kinases including cdc2. Recent data suggest an important role for the p53-regulated WIP1 phosphatase that acts as a critical dampener of DNA damage signaling in cancer. In human cancer, researchers have found p53 to be commonly mutated, indicating that this checkpoint is a critical barrier to tumor formation. In addition, sporadic and familial mutations in the DNA-repair proteins such as the BRCA-family, ATM, and the Fanconi Anemia proteins further highlight this as a 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.
• Al-Ejeh F, Kumar R, Wiegmans A, Lakhani SR, Brown MP, Khanna KK (2010) Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes. Oncogene 29(46), 6085–98.
• Boutros R, Lobjois V, Ducommun B (2007) CDC25 phosphatases in cancer cells: key players? Good targets? Nat. Rev. Cancer 7(7), 495–507.
• Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol. Cell 40(2), 179–204.
• Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev. 26(12), 1268–86.
• Huen MS, Sy SM, Chen J (2010) BRCA1 and its toolbox for the maintenance of genome integrity. Nat. Rev. Mol. Cell Biol. 11(2), 138–48.
• Junttila MR, Evan GI (2009) p53--a Jack of all trades but master of none. Nat. Rev. Cancer 9(11), 821–9.
• Kee Y, D'Andrea AD (2010) Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes Dev. 24(16), 1680–94.
• Lens SM, Voest EE, Medema RH (2010) Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat. Rev. Cancer 10(12), 825–41.
• Nam EA, Cortez D (2011) ATR signalling: more than meeting at the fork. Biochem. J. 436(3), 527–36.
• 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.