1. Cell-cycle checkpoint activation downstream of ATM and ATR
Cell-cycle checkpoint activation downstream of ATM and ATR. Induction of DSBs by IR activates ATM, which phosphorylates MDM2 preventing p53 proteasomal degradation. ATM also activates, via phosphorylation, CHK2, which, in turn, phosphorylates CDC25A to inactivate its phosphatase activity and block CyclinE-CDK2-Rb–mediated S-phase entry. The stabilization of p53 is accompanied by ATM- and CHK2-phosphorylation which activate transcription of p53 target genes, such as p21. As a CDK inhibitor p21 blocks CyclinD-CDK4/5 and CyclinE-CDK2 and, therefore, S-phase entry. Activated ATM also phosphorylates SMC1 and NBS1 proteins that slow progression through S-phase by poorly defined mechanisms. DNA damage incurred during S-phase (by IR or UV) may create ssDNA. This ssDNA is coated by RPA recruiting ATR via its coactivator, ATRIP. Active ATR phosphorylates CHK1, which inactivates CDC25C. ATM activity and p53-induction of σ also inactivate CDC25C. Inactive CDC25C cannot remove inhibitory phosphate groups on CDK1 and therefore blocks CyclinB-mediated transition to mitosis. Crosstalk between ATM and ATR leads to simultaneous activation of many of these pathways, as described in the text.
Source: Genomic Stability and DNA Repair, The Basic Science of Oncology, 5e
Citation: Tannock IF, Hill RP, Bristow RG, Harrington L. The Basic Science of Oncology, 5e; 2016 Available at: Accessed: September 30, 2017
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