Figure 8.
A model for the regulation of ATM by PP2A. (A) In the absence of DNA damage, (1) dimers of ATM undergo a basal level of autophosphorylation (at serine 1981) that is (2) removed by bound PP2A. (B) The addition of OA to cells (1) inhibits PP2A protein phosphatase activity, allowing (2) autophosphorylated ATM to accumulate in the absence of DSBs and without an increase in protein kinase activity. (C) IR causes (1) dissociation of PP2A from ATM in a mechanism that requires the protein kinase activity of ATM, leading to (2) accumulation of autophosphorylated ATM. Independently, IR causes the recruitment of the MRN complex (possibly with MDC1 and other proteins) to sites of DNA damage. Autophosphorylated ATM is then (3) recruited to the DSB, possibly resulting in full activation of ATM protein kinase activity, followed by (4) phosphorylation of histone H2AX across several megabases of DNA and (5) localized phosphorylation of ATM substrates at IR-induced foci.