Ghezraoui H Oliveira C Becker JR Bilham K Moralli D Anzilotti C Fischer R Deobagkar-Lele M Sanchiz-Calvo M Fueyo-Marcos E Bonham S Kessler BM Rottenberg S Cornall RJ Green CM Chapman JR 2018 53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin class-switch recombination1,2, and reduced fidelity of long-range V(D)J recombination3. The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres4, and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis5-7. Cells that lack core non-homologous end joining proteins are profoundly radiosensitive8, unlike 53BP1-deficient cells9,10, which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin-a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)-as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway. application/pdf https://sonar.ch/global/documents/185130 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41586-018-0362-1 info:eu-repo/semantics/altIdentifier/pmid/30046110 info:eu-repo/semantics/openAccess Nature. - 2018 Animals Cell Cycle Proteins Cell Line DNA DNA Breaks, Double-Stranded DNA End-Joining Repair DNA, Single-Stranded DNA-Binding Proteins Female Humans Immunoglobulin Class Switching Mad2 Proteins Male Mice Mice, Inbred C57BL Multiprotein Complexes Mutation Tumor Suppressor p53-Binding Protein 1 V(D)J Recombination 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. http://purl.org/coar/resource_type/c_6501