(A) Proposed modes of action of the S. acidocaldarius Mre11/Rad50 (M/R) complex during DNA repair events. Associations with the homologous chromosome may form via Velcro®-like interchromosomal connections between the Rad50 zinc-hooks and coiled-coiled regions (blue shaded region). M/R oligomers may also link the broken DNA termini while the homologous chromosome remains held in proximity by Rad50 intermolecular associations. The M/R protein complexes scan the DNA double-helix and slide a towards a ds-break, facilitated by associations with the Rad50 coiled-coils. We speculate that M/R unwinding activity would facilitate the strand-invasion steps of HR. In S. acidocaldarius, the HerA–NurA DNA end-resection machinery generates long-range 3′ ss-DNA overhangs. The intrinsic unwinding activity of the M/R complex may open the DNA duplex on the homologous chromosome to facilitate D-loop formation and strand-invasion by the RadA proteo-filament, although this hypothesis requires experimental verification. (B) Real-time FS-AFM imaging of DNA binding and translocation following association with the Rad50 coiled-coil apices of the wild-type M/R complex. Selected images of the S. acidocaldarius M/R complex captured during Fast Scan-AFM imaging as described by Zabolotnaya et al. [43]. M/R can interact with DNA substrates via the Rad50 coiled coils apices (cartoons below images, red shaded circles). Examination of individual Rad50 apices reveals a pattern of alternate binding and disengagement from the DNA substrate resulting in the intermittent movement that displaces the DNA strand from left to right (cartoons, blue dotted arrows). A second M/R protein oligomer arrives at the observed area (24:30) and binds to another region of the DNA strand via the ends of Rad50 coiled coils making two different contact points (blue shaded circles, 1 & 2), as depicted in the cartoons. This interaction causes a transient pulling of the DNA substrate towards the newly arrived protein complex at the first contact point (blue shaded circle, 1) (24:30–25:00). These dramatic ATP-dependent movements seem consistent with an active DNA scanning mechanism. (C) Model proposed by Kashammer et al. [94] for the sensing and processing of DNA ends by E. coli MR. Upon binding at an internal DNA site the M/R complex enters into a scanning mode (with relaxed coiled-coils) until a blocked end or dsDNA break is encountered, upon which the coiled-coils undergo a ring-to-rod transition forming the high-affinity cutting state at or near DNA ends. (D) Illustration of SMC family ATP-dependent coiled-coil transitions from ring-to-rod conformational changes, illustrating a putative model for a DNA loop extrusion mechanism by an SMC protein (as proposed in [79] (see Figure 4).