Figure 2

Schematic representation of the DNA damage-signaling that leads to activation of cell cycle checkpoints or apoptosis. (A) Examples of proteins involved in the different steps of DNA damage signaling are shown. DNA lesions are recognized by sensors (e.g ATM), and mediators (e.g 53BP1) serve to amplify the signaling of DNA damage. Next, proteins including CHK2 serve to transduce the DNA damage signals. Finally, effectors (e.g p53) are required to trigger the appropriate DNA damage cellular responses that include apoptosis, senescence or cell cycle arrest or delay that allow cells to repair their damaged DNA. (B) In response to DSBs and/or DNA replication failure, activated ATM and/or ATR phosphorylate the CHK2 and CHK1. Activated ATM, ATR and CHK2 also phosphorylate p53, thus increasing its stability and activation. Activated p53 transactivates the p21 that inhibits the cyclin-dependent-kinases and delays the G1/S transition. In the case the damage DNA is beyond repair, p53 can promote apoptosis of the damaged cells through the transactivation of its transcriptional targets including the Bax, Puma and Noxa. CHK1 is essential for S and G2/M checkpoints activation. CDC25C inactivation and WEE1 activation through their phosphorylation by CHK1 result in the inhibition of CDC2/cyclin B activity and G2/M arrest. CDC25C dephosphorylates CDC2 leading to its activation [177]. In response to DNA damage, CHK1 phosphorylates CDC25C allowing its interaction with 14-3-3 and inhibition of its phosphatase activity [178, 179]. CHK1 also phosphorylates WEE1, affecting its distribution through interaction with 14-3-3. Finally, CHK1 also phosphorylates CDC25A leading to CDK2 inactivation and delayed intra-S phase [180].