ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair

Rad50 ABC-ATPase complex with Mre11 nuclease is essential for dsDNA break repair, telomere maintenance, and ataxia telangiectasia mutated kinase checkpoint signaling. How Rad50 affects Mre11 functions, and how ABC-ATPases communicate nucleotide binding and ligand states across long distances and among protein partners, has remained obscure. Here, structures of Mre11–Rad50 complexes define the Mre11 2-helix Rad50 binding domain (RBD) that forms a 4-helix interface with Rad50 coiled-coils adjoining the ATPase core. Newly identified effector and basic-switch helix motifs extend the ABC-ATPase signature motif to link ATP-driven Rad50 movements to coiled-coils binding Mre11, implying a ~30 Å pull on the linker to the nuclease domain. Both RBD and basic-switch mutations cause clastogen sensitivity. Collective results characterize flexible ATP-dependent Mre11 regulation, defects in cancer-linked RBD mutations, conserved superfamily basic-switches and motifs effecting ATP-driven conformational change, and a unified comprehension of ABC-ATPase activities.