Chapter 16 Chk1 and Chk2 as Checkpoint Targets

DNA damage checkpoint response is initiated to arrest cell cycle progression so that DNA repair can take place and, thereby, prevents accumulation and propagation of DNA damage. In checkpoint response, Chk1 and Chk2 have major roles, primarily in arresting cells in S and G2 phase of the cell cycle. However, Chk1 appears to be the more critical player, with Chk2 playing an acces- sory role. Since S and G2 arrest are pro-survival events, a major effort has been devoted to the devel- opment of Chk1 inhibitors, some of which have en- tered clinical trials as chemo- and radio-sensitizers. On the other hand, Chk2 potentiates p53-dependent apoptosis, and inhibitors targeting this kinase may afford protection against normal tissue injury during cancer therapy.