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3d Structure of a DNA Damage Repair Complex

28.11.2007
The work was co directed by Dr. Aidan Doherty from the Sussex Centre for Genome Damage and Stability in the UK and by Dr. Luis Blanco from the Centro de Biología Molecular Severo Ochoa (CSIC-UAM).

This is the first study that shows the 3D structure of a molecular complex found in the bacteria Mycobacterium tuberculosis that repairs DNA damage. According to the biochemical data, this reflects a stage of the search for compatible microhomologies. This is the process of seeking non complementary extremes of DNA that would never link under normal conditions, known as non-homologous end joining (NHEJ). Among the Spanish participating researchers are Dr. Raquel Juárez Santos, and Dr. Angel J. Picher Serantes.

The double strand breaking of DNA is considered the most lethal kind of damage for our genome, since an error in its repair potentially represents cell death or tumour growth. Non-homologous end joining is a repair process for the double strand breaking of DNA which can operate at any stage of the cellular cycle, and it is essential in maintaining the genome stability in mammals. The process uses a combination of proteins responsible for the protection and maintenance of the proximity of the ends as well as all the actions necessary to repair the rupture. As an analogy, NHEJ operates like an adhesive kit that cleans the damaged area, fills the missing parts, and glues together the loose ends, even if is inevitable that some nucleotides are changed or lost in the process. A potential hazard of this mechanism is simultaneous ruptures, since it is possible that the strands are confused and the wrong strands are glued together, and such a translocation could activate an oncogene.

This study, published in Science magazine, identifies the structural bases of the NHEJ process in the DNA of the bacteria Mycobacterium tuberculosis, and shows for the first time the 3D structure of a NHEJ repairing complex. Up until now, there was little information about the different processing activities that occur in sequential coordination during the NHEJ, either about the independent proteins of mammals, or the different parts of the same protein like in bacteria. The union of the extremities shown in the 3D structure and described in this study, shows the stage of alignment of the ends, prior to the processing by the activity of nuclease (DNA cleaver), polymerase (DNA synthesis) and ligase (DNA binding), all carried out by the enzyme LigD (DNA repair) in the case of bacteria. This study can be extrapolated to the NHEJ of mammals.

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From a more applied point of view, this analysis identifies the polymerization of the bacterial LigD as a possible target to hamper the repair process of double strand breaks in these organisms. It has been proven that the NHEJ is a source of genetic variability in bacteria, necessary for their adaptation and survival in genotoxic (toxic for DNA) environments. The selective elimination of this process could have applications such as treatments that avoid the generation of antibiotic resistant bacteria.

Oficina de Cultura Científica | alfa
Further information:
http://dx.doi.org/10.1126/science.1145112

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