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 oncogenesis5,6,7. 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.
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We thank members of the Chapman, Green, Cornall and Rottenberg laboratories for discussions; T. Humphrey for comments on the manuscript; D. Adams for the Rev7tm1a mouse strain; S. Boulton for 53bp1−/− mice; J. Grimes and R. Nolan for assistance with protein modelling and statistics; and B. Davies, M. Barazas, B. Reina-San-Martin, B. Deplancke, L. Vasilieva, A. Nussenzweig and E. Callen-Moreau for reagents and advice. H.G. thanks K. Ghezraoui for her unwavering support and encouragement. This project was funded by Medical Research Council (MRC) Grant (MR/M009971/1) and Cancer Research UK Career Development Fellowship (C52690/A19270) awarded to J.R.C. C.A. and M.D.-L. are funded by the MRC, R.J.C. is a Principal Investigator of the MRC Human Immunology Unit. R.F. and B.M.K. are supported by the Kennedy Trust and the John Fell Fund. M.S.-C. and E.M.-F. were supported by ERASMUS+ fellowships. The Wellcome Centre for Human Genetics is supported by Wellcome grant (090532/Z/09/Z).
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Nature Communications (2018)