Figure 5.

Non-canonical mechanism of activation of AMPK in the cell nucleus by treatments that cause DNA damage. Agents such as ionizing radiation, cytotoxic drugs or DNA synthesis inhibitors cause DNA damage, either directly or following replicative stress. This causes release of Ca²⁺ ions within the nucleus, which activates CaMKK2 within that compartment. AMPK complexes containing AMPK-α1 also appear to translocate from the cytoplasm to the nucleus, where they are activated by CAMKK2-dependent phosphorylation at Thr172. AMPK activation enhances cell survival; it causes a G1 phase cell cycle arrest, and triggers phosphorylation of EXO1, limiting its ability to cause excessive resection at stalled replication forks. As indicated by question marks, several aspects of this mechanism remain unresolved: (i) how is the DNA damage sensed? (ii) what is the source of Ca²⁺ and its mechanism of release into the nucleus? and (iii) how is the translocation of AMPK-α1 to the nucleus achieved and regulated? The source of nuclear Ca²⁺ release is shown here as the nuclear envelope, but this is also unconfirmed.