Figure 5. Crosstalk and regulation among PIKKs. (A) Possible models of the regulation of PIKK signaling by the RUVBL1/2 complex. (a) The RUVBL1/2 complex integrates each PIKK signaling as an upstream regulator and induces proper stress responses. (b) When multiple PIKKs cooperatively function in response to stress signals, the RUVBL1/2 complex assists this process and coordinates multiple PIKK signals (the left model). The RUVBL1/2 complex coordinates the cross-regulation among PIKKs [see also (B)] thereby induce proper stress responses (the right model). The atomic structure of RUVBL1 is derived from reference.⁸⁴ (B) Cross-regulation among PIKKs. Several regulatory mechanisms among PIKKs have been observed. (a) Interdependent activation of ATM and ATR in response to DNA damage. (b) Regulation of other PIKK by direct phosphorylation: DNA-PKcs is phosphorylated by ATM and ATR in response to DNA damage stress to regulate cellular radio-resistance and NHEJ. (c) Regulation of other PIKK levels: DNA-PKcs and mTOR are required for the maintenance of ATM abundance. DNA-PKcs is also involved in the maintenance of SMG-1 abundance. (d) Regulation of other PIKK signals by indirect phosphorylations: Both upstream and downstream factors of mTORC1 signal are ATM/ATR substrates and mTORC1 signal is downregulated by DNA damage stresses. (C) Shared substrates among PIKKs. Histone H2Ax, p53, and Upf1 are shared substrates of DNA-PKcs, ATM, ATR and SMG-1. 4EBP and Akt, two well known mTOR substrates, are also phosphorylated by ATM and DNA-PKcs respectively.