The cell cycle is a highly coordinated process that is controlled by multiple protein components on which exogenous and endogenous stimuli converge (1). The cell cycle has five main phases (G0, G1, S, G2 and M) at which checkpoint mechanisms ensure the fidelity of DNA replication, repair, and division processes. The signaling pathways impinging upon the different cell cycle phases are central for the cell's decision when to commit to DNA synthesis and proliferation versus growth arrest, DNA repair or apoptosis.

Cell cycle arrest in response to DNA damage is an important part of the mechanism used in the cell cycle to maintain genomic integrity and the cell cycle checkpoints act as control mechanisms to restrain cell cycle transition after DNA damage. The G1/S cell cycle checkpoint controls the passage of cells into the DNA synthesis phase. Two cyclin-dependent protein kinases, CDK4/6-cyclin D and CDK2-cyclin E, together with the transcription complexes that includes Rb-HDAC and E2F-DP1 are critical for controlling this checkpoint (2).

The G2/M cell cycle checkpoint prevents the cell from entering mitosis during DNA damage and CDK1-cyclin B plays a critical role in this phase of the cell cycle (3). In the presence of DNA damage, activation of DNA-PK, ATM and ATR occurs which allows these protein kinases to phosphorylate p53 (4). This leads to the dissociation of p53 from MDM2, thereby activating its transcriptional activity to synthesize CDK1 inhibitory proteins. In addition, DNA damage leads to the activation of Chk1 and Chk2 which can phosphorylate and inhibit the activity of CDC25, thereby preventing the activation of CDK1. The signaling pathways feeding into the cell cycle incorporate various oncogenes and tumor suppressors and are therefore a central target for genetic alterations in human cancers (5).Defects in many of the proteins that regulate the cell cycle have been implicated in cancer formation and progression. Key among these are p53, the retinoblastoma protein (Rb) and its related proteins, p107 and Rb2/p130, and CDK inhibitors (p15, p16, p18, p19, p21, p27). The Rb (Rb/p16(INK4a)/cyclin D1) and p53 (p14(ARF)/MDM2/p53) pathways are the two main cell-cycle control pathways frequently targeted in tumorigenesis, and the alterations occurring in each pathway depend on the tumor type (6).

REFERENCES
1. Mercer, W. E.: Checking on the cell cycle. J Cell Biochem Suppl. 1998;30-31:50-4.
2. Bartek, J. et al: Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr Opin Cell Biol. 2001 Dec;13(6):738-47.
3. Stark, G. R. et al: Analyzing the G2/M checkpoint. Methods Mol Biol. 2004;280:51-82.
4. Okorokov, A. L.: p53 in a crosstalk between DNA repair and cell cycle checkpoints. Cell Cycle. 2003 May-Jun;2(3):233-5.
5. Dash, B. C. et al: Cell cycle checkpoint control mechanisms that can be disrupted in cancer. Methods Mol Biol. 2004;280:99-161.
6. Macaluso, M. et al: Modulation of cell cycle components by epigenetic and genetic events. Semin Oncol. 2005 Oct;32(5):452-7.