Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA (original) (raw)
- Letter
- Published: 15 September 2005
- Martijn de Jager2,
- Nynke H. Dekker1,
- Roland Kanaar2,3,
- Claire Wyman2,3 &
- …
- Cees Dekker1
Nature volume 437, pages 440–443 (2005)Cite this article
- 2141 Accesses
- 210 Citations
- 3 Altmetric
- Metrics details
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 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Connelly, J. C. & Leach, D. R. Tethering on the brink: the evolutionarily conserved Mre11–Rad50 complex. Trends Biochem. Sci. 27, 410–418 (2002)
Article CAS Google Scholar - de Jager, M. et al. Human Rad50/Mre11 is a flexible complex that can tether DNA ends. Mol. Cell 8, 1129–1135 (2001)
Article CAS Google Scholar - 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)
Article CAS Google Scholar - 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)
Article ADS CAS Google Scholar - 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)
Article ADS CAS Google Scholar - 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)
Article CAS Google Scholar - 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)
Article CAS Google Scholar - Wyman, C. & Kanaar, R. Chromosome organization: reaching out to embrace new models. Curr. Biol. 12, R446–R448 (2002)
Article CAS Google Scholar - 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)
Article CAS Google Scholar - 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)
Article CAS Google Scholar - 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)
Article CAS Google Scholar
Acknowledgements
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.
Author information
Authors and Affiliations
- Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ, Delft, The Netherlands
Fernando Moreno-Herrero, Nynke H. Dekker & Cees Dekker - Department of Cell Biology and Genetics,
Martijn de Jager, Roland Kanaar & Claire Wyman - Department of Radiation Oncology, Erasmus MC, PO Box 1738, 3000 DR, Rotterdam, The Netherlands
Roland Kanaar & Claire Wyman
Authors
- Fernando Moreno-Herrero
You can also search for this author inPubMed Google Scholar - Martijn de Jager
You can also search for this author inPubMed Google Scholar - Nynke H. Dekker
You can also search for this author inPubMed Google Scholar - Roland Kanaar
You can also search for this author inPubMed Google Scholar - Claire Wyman
You can also search for this author inPubMed Google Scholar - Cees Dekker
You can also search for this author inPubMed Google Scholar
Corresponding authors
Correspondence toClaire Wyman or Cees Dekker.
Ethics declarations
Competing interests
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Supplementary information
Rights and permissions
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
- Received: 21 January 2005
- Accepted: 19 June 2005
- Issue Date: 15 September 2005
- DOI: https://doi.org/10.1038/nature03927
This article is cited by
Chemo-mechanical forces modulate the topology dynamics of mesoscale DNA assemblies
- Deepak Karna
- Eriko Mano
- Hanbin Mao
Nature Communications (2023)
Rad50 zinc hook functions as a constitutive dimerization module interchangeable with SMC hinge
- Hisashi Tatebe
- Chew Theng Lim
- Asako Furukohri
Nature Communications (2020)
The condensin holocomplex cycles dynamically between open and collapsed states
- Je-Kyung Ryu
- Allard J. Katan
- Cees Dekker
Nature Structural & Molecular Biology (2020)
Eukaryotic Rad50 functions as a rod-shaped dimer
- Young Bong Park
- Marcel Hohl
- Yunje Cho
Nature Structural & Molecular Biology (2017)
Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence
- Ruud W. J. Meijers
- Katarzyna Dzierzanowska-Fangrat
- Anton W. Langerak
Journal of Clinical Immunology (2017)
Editorial Summary
Atherosclerosis induction
Atherosclerotic plaques form when blood flow is disturbed and unusual patterns of mechanical stress are applied to the blood vessel wall. The endothelial cells lining these vessels play an important role in the development of the disease. A study using cultured aortic endothelial cells now shows that three proteins expressed in endothelial cells form a mechanosensory complex, and each one has distinct functions in transducing mechanical force into a biochemical signal inside the cell. This can explain how blood flow stimulates endothelial cell responses and how atherosclerotic plaques might be initiated.