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 molecules2,3. 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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Connelly, J. C. & Leach, D. R. Tethering on the brink: the evolutionarily conserved Mre11–Rad50 complex. Trends Biochem. Sci. 27, 410–418 (2002)
de Jager, M. et al. Human Rad50/Mre11 is a flexible complex that can tether DNA ends. Mol. Cell 8, 1129–1135 (2001)
Wiltzius, J. J. W., Hohl, M., Fleming, J. C. & Petrini, J. H. J. The Rad50 hook domain is a critical determinant of Mre11 complex functions. Nature Struct. Mol. Biol. 12, 403–407 (2005)
van Noort, J. et al. The coiled-coil of the human Rad50 DNA repair protein contains specific segments of increased flexibility. Proc. Natl Acad. Sci. USA 100, 7581–7586 (2003)
Hopfner, K. P. et al. The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. Nature 418, 562–566 (2002)
Hopfner, K. P. et al. Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101, 789–800 (2000)
Hopfner, K. P. et al. Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50 ATPase. Cell 105, 473–485 (2001)
Wyman, C. & Kanaar, R. Chromosome organization: reaching out to embrace new models. Curr. Biol. 12, R446–R448 (2002)
de Jager, M. et al. Differential arrangements of conserved building blocks among homologs of the Rad50/Mre11 DNA repair protein complex. J. Mol. Biol. 339, 937–949 (2004)
de Jager, M. et al. DNA-binding and strand-annealing activities of human Mre11: implications for its roles in DNA double-strand break repair pathways. Nucleic Acids Res. 29, 1317–1325 (2001)
Stracker, T. H., Theunissen, J. W., Morales, M. & Petrini, J. H. J. The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair (Amst.) 3, 845–854 (2004)
We thank T. Paull for the gift of the baculoviruses producing hRad50, hMre11 and hNbs1, and R. Seidel for useful discussions. F.M.-H. is supported by a postdoctoral fellowship from La Fundación Ramón Areces. M.d.J. is supported by an EUR fellowship from the Erasmus MC. This project is supported in part by a grant from NWO-FOM/ALW (Netherlands Organization for Scientific Research) to R.K., C.W. and C.D. Work in the laboratories of R.K. and C.W. is supported by grants from the European Commission, NWO and the Dutch Cancer Society. Work in the laboratory of C.D. and N.D. acknowledges support from FOM and NWO.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
The hR/M complexes move along the DNA while following the contour of the DNA molecule. (PDF 103 kb)
Text descriptions to accompany the below Supplementary Movies. (DOC 19 kb)
Atomic force microscopy movie of a free hR/M complex imaged in buffer. (AVI 4034 kb)
Dynamic transition between the architecture of DNA-bound hR/M and DNA-free hR/M. (AVI 3842 kb)
About this article
Cite this article
Moreno-Herrero, F., de Jager, M., Dekker, N. et al. Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA. Nature 437, 440–443 (2005). https://doi.org/10.1038/nature03927
Nature Communications (2020)
Cellular and Molecular Life Sciences (2020)
Functional and structural insights into the MRX/MRN complex, a key player in recognition and repair of DNA double-strand breaks
Computational and Structural Biotechnology Journal (2020)
Journal of Molecular Biology (2020)
Metal Exchange in the Interprotein Zn II ‐Binding Site of the Rad50 Hook Domain: Structural Insights into Cd II ‐Induced DNA‐Repair Inhibition
Chemistry – A European Journal (2020)