Cell Cycle Checkpoints, Genomic Integrity, and Cancer

ATM Is Activated in Response toN-Methyl-N′-nitro- N-nitrosoguanidine-induced DNA Alkylation

“…Genotoxic events activate a number of signaling pathways that serve, for example, to activate DNA repair mechanisms, halt cell cycle progression and/or trigger advancement into apoptosis (10,37,38). Although all genotoxins produce such general responses, the mechanisms that govern response to divergent forms of DNA damage are potentially diverse themselves.…”

ATM-dependent Phosphorylation of Human Rad9 Is Required for Ionizing Radiation-induced Checkpoint Activation

“…These checkpoint controls prevent damaged DNA from being replicated or distributed into daughter cells prior to the completion of DNA repair, thus helping to maintain genomic integrity. Failure of this cell cycle surveillance mechanism can cause genomic instability that eventually leads to cancer formation in mammals (5,6).…”

G2 Checkpoint Kinase Inhibitors Exert Their Radiosensitizing Effects Prior to the G2/M Transition

“…Radiotherapy and DNA-damaging chemotherapeutic agents are frequently used for cancer treatment, and combination treatment with checkpoint inhibitors has been proposed as a means to increase tumor killing while leaving normal cells relatively unharmed. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Several G 2 checkpoint inhibitors have been identified to date, including the methylxanthines caffeine and pentoxifylline that inhibit the checkpoint kinases ATM and ATR 2,22,23 and small molecule and peptide inhibitors of the downstream kinases Chk1 6,24-27 and Chk2. [28][29][30] Several Chk1 inhibitors are currently in preclinical development or early clinical trials.…”