Cell Cycle Control: G2/M DNA Damage Checkpoint
Pathway Description:
The G2/M DNA damage checkpoint serves to prevent the cell from entering mitosis (M-phase) if the genome is damaged. To this end, the activity of the cdc2-cyclin B complex is pivotal in regulating this transition. During the G2-phase, cdc2 is maintained in an inactive state by the kinases Wee1 and Myt1. As cells approach M-phase, the phosphatase cdc25 is activated by phosphorylation which in turn activates cdc2, establishing a feedback amplification loop that efficiently drives the cell into mitosis. Importantly, DNA damage activates the DNA-PK/ATM/ATR kinases, initiating two parallel cascades that inactivate cdc2-cyclin B complex. The first cascade rapidly inhibits progression into mitosis: the Chk kinases phosphorylate and inactivate cdc25, which can no longer activate cdc2. The slower second parallel cascade involves phosphorylation of p53 and allows for its dissociation from MDM2, which activates DNA binding and transcriptional regulatory activity. Further p53 activation is accomplished through acetylation by p300/PCAF. The downstream genes that are regulated by p53 constitute effectors of this second cascade. They include 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 (CDK1). In human cancer, p53 is commonly mutated indicating that this checkpoint is a critical barrier to tumor formation. In addition, sporadic as well as familiar mutations in the DNA-repair proteins such as the BRCA-family, ATM and the Fanconi Anemia proteins further support this notion.
Selected Reviews:
- Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3(5), 421–9.
- Harrison JC, Haber JE (2006) Surviving the breakup: the DNA damage checkpoint. Annu. Rev. Genet. 40, 209–35.
- Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432(7015), 316–23.
- Kohn KW, Pommier Y (2005) Molecular interaction map of the p53 and Mdm2 logic elements, which control the Off-On switch of p53 in response to DNA damage. Biochem. Biophys. Res. Commun. 331(3), 816–27.
- Sengupta S, Harris CC (2005) p53: traffic cop at the crossroads of DNA repair and recombination. Nat. Rev. Mol. Cell Biol. 6(1), 44–55.
- Venkitaraman AR (2004) Tracing the network connecting BRCA and Fanconi anaemia proteins. Nat. Rev. Cancer 4(4), 266–76.
- Wahl GM, Carr AM (2001) The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nat. Cell Biol. 3(12), E277–86.
CST would like to thank Dr. Hans Widlund, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, for contributing to this diagram.
created November 2002 • revised January 2007
