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p53-Dependent G1 DNA Damage Response

Most of the damage-induced modifications of p53 are dependent on the ATM kinase. The first link between ATM and p53 was predicted based on the earlier studies that showed that AT cells exhibit a reduced and delayed induction of p53 following exposure to IR (Kastan et al, 1992 and Khanna and Lavin, 1993).Under normal conditions, p53 is a short-lived protein. The MDM2 protein, usually interacts with p53 (Haupt et al, 1997 and Kubbutat et al, 1997), and by virtue of its E3 ubiquitin ligase activity, shuttles p53 to the cytoplasm and mediates its degradation by the ubiquitin-proteasome machinery. Upon detection of DNA damage, the ATM kinase mediates the phosphorylation of the Mdm2 protein to block its interaction with p53. Also, phosphorylation of p53 at multiple loci, by the ATM kinase and by other kinases activated by the ATM kinase, stabilizes and activates the p53 protein.The p53 protein activates the transcription of cyclin-dependent kinase inhibitor, p21. p21 inactivates the CyclinE:Cdk2 complexes, and prevent entry of the cell into S phase, leading to G1 arrest. Under severe conditions, the cell may undergo apoptosis.

from REACTOME source record: R-HSA-69563
Type: pathway
Taxonomic scope
organism-specific biosystem
Homo sapiens

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