1. The Kimmel Center for Biology and Medicine of the Skirball Institute and Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
2. Department of Gene and Cell Medicine, The Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA
3. College of Veterinary Medicine, Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824, USA
4. Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
5. These authors contributed equally to this work.
6. Present address: Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, California 92121, USA.

Correspondence to: David B. Roth¹ Correspondence and requests for materials should be addressed to D.B.R. (Email: roth@saturn.med.nyu.edu).

Mammalian cells repair DNA double-strand breaks (DSBs) through either homologous recombination or non-homologous end joining (NHEJ). V(D)J recombination, a cut-and-paste mechanism for generating diversity in antigen receptors, relies on NHEJ for repairing DSBs introduced by the Rag1–Rag2 protein complex. Animals lacking any of the seven known NHEJ factors are therefore immunodeficient¹. Nevertheless, DSB repair is not eliminated entirely in these animals: evidence of a third mechanism, 'alternative NHEJ', appears in the form of extremely rare V(D)J junctions^{2, 3, 4} and a higher rate of chromosomal translocations^{5, 6}. The paucity of these V(D)J events has suggested that alternative NHEJ contributes little to a cell's overall repair capacity, being operative only (and inefficiently) when classical NHEJ fails. Here we find that removing certain portions of murine Rag proteins reveals robust alternative NHEJ activity in NHEJ-deficient cells and some alternative joining activity even in wild-type cells. We propose a two-tier model in which the Rag proteins collaborate with NHEJ factors to preserve genomic integrity during V(D)J recombination.

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