1. Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
2. Department of Cell Biology and Genetics and
3. Department of Radiation Oncology, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, The Netherlands

Correspondence to: Claire Wyman^2,3Cees Dekker¹ Correspondence and requests for materials should be addressed to C.D. (Email: dekker@mb.tn.tudelft.nl) and C.W. (Email: c.wyman@erasmusmc.nl).

Abstract

The human Rad50/Mre11/Nbs1 complex (hR/M/N) functions as an essential guardian of genome integrity by directing the proper processing of DNA ends, including DNA breaks¹. This biological function results from its ability to tether broken DNA molecules^{2, 3}. hR/M/N's dynamic molecular architecture consists of a globular DNA-binding domain from which two 50-nm-long coiled coils protrude. The coiled coils are flexible⁴ and their apices can self-associate⁵. The flexibility of the coiled coils allows their apices to adopt an orientation favourable for interaction. However, this also allows interaction between the tips of two coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. Here we show that the dynamic architecture of hR/M/N is markedly affected by DNA binding. DNA binding by the hR/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favours intercomplex associations needed for DNA tethering. The hR/M/N complex thus is an example of a biological nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nm distant.

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