ATM Kinase,”stress-activated kinasestarting point: have very little p53 in our cells (it is a constitutively active gene) b/c cells have specific ubiquitin ligase that targets p53 (Mdm2)directly phosphorylates p53, this phosphorylation stabilizes it. P53 acts as a tetramer (levels starting to rise…have to allow concentration to rise where it can work)have to get Mdm2 out of the way, so ATM also phosphorylates Mdm2, which activates ___ ligase activity (arf?)stabilizing p53 phosphorylation, inactivating ubiquitin ligase to get it out of the way (so p53 levels can increase–>p53 DNA binding protein has different sequences that it binds to w/ different affinities)P53 sites associated with P21cip (stops cell cycle wherever DNA damage takes place, but doesn’t stop damage)activates genes encoding proteins that can fix the damage (once p53 gets to intermediate levels) and if damage fixed, inactivate ATM, shut off kinase, phosphatases come in, dephosphorylate p53, and dephosphorylate Mdm2shuts off P21cip, cell cycle takes off, back to normalif damage ISN’T fixed, p53 levels keep rising

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P53,”most important tumor suppressorthe weak point of the system-the single point of failure; p53 is protein that links DNA damage to activating the checkpoint throughout the cycle (because DNA damage can occur at any time), stopping the cell cycle, repairing the damage and initiating apoptosis(interactions with ATM kinase, Mdm2, and Chkpoints1&2)In low concentration, p53 stops cell cycle. Damage unstopped b/c don’t activate repair genes (not high enough affinity) damage persists, repair genes activated, cell cycle arrest transientIf inactivated, damage accumulates

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