title: Envisioning the dynamics and flexibility of Mre11-Rad50-Nbs1 complex to decipher its roles in DNA replication and repair.
abstract: The Mre11-Rad50-Nbs1 (MRN) complex is a dynamic macromolecular machine that acts in the first steps of DNA double strand break repair, and each of its components has intrinsic dynamics and flexibility properties that are directly linked with their functions. As a result, deciphering the functional structural biology of the MRN complex is driving novel and integrated technologies to define the dynamic structural biology of protein machinery interacting with DNA. Rad50 promotes dramatic long-range allostery through its coiled-coil and zinc-hook domains. Its ATPase activity drives dynamic transitions between monomeric and dimeric forms that can be modulated with mutants modifying the ATPase rate to control end joining versus resection activities. The biological functions of Mre11's dual endo- and exonuclease activities in repair pathway choice were enigmatic until recently, when they were unveiled by the development of specific nuclease inhibitors. Mre11 dimer flexibility, which may be regulated in cells to control MRN function, suggests new inhibitor design strategies for cancer intervention. Nbs1 has FHA and BRCT domains to bind multiple interaction partners that further regulate MRN. One of them, CtIP, modulates the Mre11 excision activity for homologous recombination repair. Overall, these combined properties suggest novel therapeutic strategies. Furthermore, they collectively help to explain how MRN regulates DNA repair pathway choice with implications for improving the design and analysis of cancer clinical trials that employ DNA damaging agents or target the DNA damage response.
authors.affiliation: Life Science Division, 1 Cyclotron Road, Berkeley, CA 94720, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Lafrance-Vanasse
authors.affiliation: Life Science Division, 1 Cyclotron Road, Berkeley, CA 94720, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Williams
authors.affiliation: Life Science Division, 1 Cyclotron Road, Berkeley, CA 94720, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: jatainer@lbl.gov.
authors.forename: John A
authors.initials: JA
authors.lastname: Tainer
mesh_terms: D017766:Acid Anhydride Hydrolases; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D006801:Humans; D000076228:MRE11 Homologue Protein; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D004247:DNA; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes
keywords: Allostery; Conformational change; CtIP; Double strand break repair; Dynamics; Mre11-Rad50-Nbs1