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Although the role of membrane anchors with large spatial separations in kinase activation is unique, similar local rearrangements of the N-lobes and C-lobes of other PIKK family members, ATM, MEC1 ATR and DNA-PK, have been reported in response to reactive oxygen species-dependent activation 34 , constitutive activating mutation (F2244L) 35 and DNA activation 36 , respectively