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Mre11-Rad50-Nbs1 conformations and the control of sensing, signaling, and effector responses at DNA double-strand breaks Williams GJ; Lees-Miller SP; Tainer JADNA Repair (Amst) 2010[Dec]; 9 (12): 1299-306Repair and integrity of DNA ends at breaks, replication forks and telomeres are essential for life; yet, paradoxically, these responses are, in many cases, controlled by a single protein complex, Mre11-Rad50-Nbs1 (MRN). The MRN complex consists of dimers of each subunit and this heterohexamer controls key sensing, signaling, regulation, and effector responses to DNA double-strand breaks including ATM activation, homologous recombinational repair, microhomology-mediated end joining and, in some organisms, non-homologous end joining. We propose that this is possible because each MRN subunit can exist in three or more distinct states; thus, the trimer of MRN dimers can exist in a stunning 6(3) or 216 states, a number that can be expanded further when post-translational modifications are taken into account. MRN can therefore be considered as a molecular computer that effectively assesses optimal responses and pathway choice based upon its states as set by cell status and the nature of the DNA damage. This extreme multi-state concept demands a paradigm shift from striving to understand DNA damage responses in separate terms of signaling, checkpoint, and effector proteins: we must now endeavor to characterize conformational and assembly states of MRN and other DNA repair machines that couple, coordinate, and control biological outcomes. Addressing the emerging challenge of gaining a detailed molecular understanding of MRN and other multi-state dynamic DNA repair machines promises to provide opportunities to develop master keys for controlling cell biology with probable impacts on therapeutic interventions.|*DNA Breaks, Double-Stranded[MESH]|*Models, Molecular[MESH]|*Protein Conformation[MESH]|Acid Anhydride Hydrolases[MESH]|Cell Cycle Proteins/metabolism[MESH]|DNA Repair Enzymes/metabolism[MESH]|DNA Repair/genetics/*physiology[MESH]|DNA-Binding Proteins/metabolism[MESH]|Dimerization[MESH]|MRE11 Homologue Protein[MESH]|Multiprotein Complexes/*metabolism[MESH]|Nuclear Proteins/metabolism[MESH]|Protein Processing, Post-Translational/genetics/*physiology[MESH]|Signal Transduction/genetics/*physiology[MESH] |
