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A combination of sensor and fastener

Structure of a key component of DNA repair determined

Munich, 04/04/2011

Double-stranded breaks constitute perhaps the most dangerous type of damage to which the genetic material DNA is prone. DSBs can be caused by radiation or environmental toxins and can lead to cell death, but they may also trigger the development of cancer. Efficient cellular repair mechanisms are therefore an essential part of the body’s defenses against malignancies. The so-called MR complex plays a central role in the repair of DSBs. A research team led by Professor Karl-Peter Hopfner at LMU‘s Genzentrum has now determined the structure of this crucial complex and thrown light on its mechanism of action. The team found that the complex acts as a sensor that closes when it encounters a DSB. “The complex itself has an open structure, which presumably allows it to recognize different sorts of break. When it reaches a break, it closes to form a ring-like structure – rather like a hand, that can open and close,” says Hopfner. In addition, the MR complex acts like a molecular fastener to hold the broken strands together. MR complexes form filaments at the broken ends of the DNA, which interdigitate to prevent the fragmented molecules from drifting apart. The complex then initiates the actual repair process by resecting the free end of one strand on each side of the break. At this point, either an appropriate mechanism is selected to repair the damage or, in cases where damage is more extensive, the process of programmed cell death is activated. The new data provide important insights into the mechanisms used by the cell to repair DSBs. They may also suggest new ways to modulate repair processes for therapeutic purposes. For example, targeted inhibition of the MR complex should make cells more sensitive to radiation, which would in turn reduce the dosage necessary for the effective treatment of cancer. (Cell, 1 April 2011)

The hereditary material DNA takes the form of double-stranded, spirally wound molecules made up of subunits called nucleotides. In the cell, these molecules form the chromosomes, which act as the repository of an organism’s genetic information. Genotoxic chemicals, X-rays and radioactivity can all cause breaks in both strands, but double-stranded breaks (DSBs) also arise during replication of the chromosomes prior to cell division. DSBs pose a serious threat to the survival of cells and organisms, because they may result in genetic mutations that can lead to diseases like leukemias. Cells have therefore evolved mechanisms for the prompt and precise repair of DSBs. In all of these repair processes, the so-called MR complex plays a central role. The complex consists of four subunits, two nucleases and two ATPases, and it acts as a sensor that recognizes DSBs. In addition, it initiates the repair process by binding to breaks and removing nucleotide subunits from one strand of the DNA duplex. The nucleotides released act as a signal for further steps in repair or, if the damage is extensive, lead to induction of programmed cell death. In humans, defects in the MR complex lead to serious medical conditions, such as Nijmegen Breakage Syndrome, which is associated with hypersensitivity to radiation.

“Despite its great significance, it was hitherto completely unclear how the MR complex actually recognizes the many different types of breaks at DNA ends, which may also be masked by other proteins,” says Hopfner. Dr. Katja Lammens, Dr. Derk Bemeleit and Carolin Möckel, who are members of Prof. Hopfner’s group, succeeded in crystallizing the complex and were then able to determine its three-dimensional structure by X-ray diffraction analysis. The structure shows that the MR complex acts like a hand or a clamp that opens and closes. In the open form of the complex, which can probably recognize broken DNA ends that are blocked by other proteins, the two ATPases are far apart. When this form reaches a break, the two ATPases are brought together, forming the closed complex. The energy for this conformational change is provided by cleavage of ATP. “This explains why ATP, the energy currency in the cell, is essential for the process – its role in the complex was previously unknown,” says Hopfner. Multiple copies of the MR complex form molecular filaments at the broken ends that interlock rather in the manner of a hook-and-loop fastener, holding the fragments on either side of the break together.

The new insights into the structure and mode of action of the MR complex are also of interest from a clinical point of view, because agents that cause DSBs play an important role in cancer therapy. Tumor cells have an abnormally high division rate and therefore tend to produce more DSBs than normal cells. Radiation and many chemotherapeutic agents induce the formation of further DSBs, eventually leading to lethal levels of damage. Thus, if one could prevent ongoing repair by specifically inhibiting the action of the MR repair complex or other proteins that participate in later steps in repair, the same killing effect could be achieved with lower dosages, making treatments less traumatic for the patient. “Another possible approach takes advantage of the fact that some DNA repair pathways are already inactivated in cancer cells, which increases the mutation rate. If one blocks the remaining pathways, the burden of damage should become so great that the cells undergo programmed cell death. Healthy cells, in contrast, might be able to compensate for the loss of the inhibited pathways,” explains Hopfner. In order to understand the function of the MR complex in greater detail, his team now wants to look more closely at how it interacts with DNA because, as Hopfner points out, “Exactly how DNA binds to the MR complex is still not understood.” (göd/PH)

The study was carried out under the auspices of two Centers of Excellence, the Center for Integrated Protein Science Munich (CiPSM) and the Munich Center for Advanced Photonics (MAP). The work was supported by the Deutsche Forschungsgemeinschaft (DFG) as part of Priority Programs (SFB) 684, 646 and TR5, and by the EU project “DNA Damage Response and Repair Mechanisms.”


"The Mre11:Rad50 Structure Shows an ATP-Dependent Molecular Clamp in DNA Double-Strand Break Repair"
K. Lammens, D. J. Bemeleit, C. Möckel, E. Clausing, A. Schele, S. Hartung, C. B. Schiller, M. Lucas, C. Angermüller, J. Söding, K. Sträßer, K.-P. Hopfner
Cell, 1 April 2011
DOI 10.1016/j.cell.2011.02.038


Professor Dr. Karl-Peter Hopfner
Faculty of Chemistry and Pharmacy
GeneCenter, LMU Munich
Phone: +49 (0) 89 / 2180 76953

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