Delineation of the Xrcc4-interacting Region in the Globular Head Domain of Cernunnos/XLF

In mammals, the majority of DNA double-strand breaks are processed by the nonhomologous end-joining (NHEJ) pathway, composed of seven factors: Ku70, Ku80, DNA-PKcs, Artemis, Xrcc4 (X4), DNA-ligase IV (L4), and Cernunnos/XLF. Cernunnos is part of the ligation complex, constituted by X4 and L4. To imp...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-08, Vol.285 (34), p.26475-26483
Main Authors: Malivert, Laurent, Ropars, Virginie, Nunez, Marcela, Drevet, Pascal, Miron, Simona, Faure, Guilhem, Guerois, Raphael, Mornon, Jean-Paul, Revy, Patrick, Charbonnier, Jean-Baptiste, Callebaut, Isabelle, de Villartay, Jean-Pierre
Format: Article
Language:English
Subjects:
Amino Acids
Binding Sites
Biochemistry, Molecular Biology
Cernunnos
Computer Simulation
Crystallography, X-Ray
DNA and Chromosomes
DNA Repair
DNA Repair Enzymes - chemistry
DNA Repair Enzymes - genetics
DNA Repair Enzymes - metabolism
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Humans
Life Sciences
Mutagenesis, Site-Directed
NHEJ
Protein Binding
Protein Conformation
Protein Domains
Protein Folding
Protein Structure
Protein Structure and Folding
Protein Structure, Tertiary
XLF
Xrcc4
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Summary:In mammals, the majority of DNA double-strand breaks are processed by the nonhomologous end-joining (NHEJ) pathway, composed of seven factors: Ku70, Ku80, DNA-PKcs, Artemis, Xrcc4 (X4), DNA-ligase IV (L4), and Cernunnos/XLF. Cernunnos is part of the ligation complex, constituted by X4 and L4. To improve our knowledge on the structure and function of Cernunnos, we performed a systematic mutagenesis study on positions selected from an analysis of the recent three-dimensional structures of this factor. Ten of 27 screened mutants were nonfunctional in several DNA repair assays. Outside amino acids critical for the expression and stability of Cernunnos, we identified three amino acids (Arg64, Leu65, and Leu115) essential for the interaction with X4 and the proper function of Cernunnos. Docking the crystal structures of the two factors further validated this probable interaction surface of Cernunnos with X4.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.138156