title: The spatial organization of non-homologous end joining: from bridging to end joining.
abstract: Non-homologous end joining (NHEJ) repairs DNA double-strand breaks generated by DNA damage and also those occurring in V(D)J recombination in immunoglobulin and T cell receptor production in the immune system. In NHEJ DNA-PKcs assembles with Ku heterodimer on the DNA ends at double-strand breaks, in order to bring the broken ends together and to assemble other proteins, including DNA ligase IV (LigIV), required for DNA repair. Here we focus on structural aspects of the interactions of LigIV with XRCC4, XLF, Artemis and DNA involved in the bridging and end-joining steps of NHEJ. We begin with a discussion of the role of XLF, which interacts with Ku and forms a hetero-filament with XRCC4; this likely forms a scaffold bridging the DNA ends. We then review the well-defined interaction of XRCC4 with LigIV, and discuss the possibility of this complex interrupting the filament formation, so positioning the ligase at the correct positions close to the broken ends. We also describe the interactions of LigIV with Artemis, the nuclease that prepares the ends for ligation and also interacts with DNA-PK. Lastly we review the likely affects of Mendelian mutations on these multiprotein assemblies and their impacts on the form of inherited disease.
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. Electronic address: to237@cam.ac.uk.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D001665:Binding Sites; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D011088:DNA Ligases / Q000737:chemistry / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004720:Endonucleases; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding
chemical_list: D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C426344:DCLRE1C protein, human; D004720:Endonucleases; D011088:DNA Ligases; D045643:DNA Repair Enzymes
keywords: Artemis, DNA ligase IV; Cernunnus; DNA-PKcs; LIG4 syndrome; Non-homologous end joining; XLF; XRCC4