title: Rag mutations reveal robust alternative end joining.
abstract: 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 immunodeficient. 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 and a higher rate of chromosomal translocations. 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.
authors: 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.
authors: Barbara
authors: B
authors: Corneo
authors: Rebecca L
authors: RL
authors: Wendland
authors: Ludovic
authors: L
authors: Deriano
authors: Xiaoping
authors: X
authors: Cui
authors: Isaac A
authors: IA
authors: Klein
authors: Serre-Yu
authors: SY
authors: Wong
authors: Suzzette
authors: S
authors: Arnal
authors: Abigail J
authors: AJ
authors: Holub
authors: Geoffrey R
authors: GR
authors: Weller
authors: Bette A
authors: BA
authors: Pancake
authors: Sundeep
authors: S
authors: Shah
authors: Vicky L
authors: VL
authors: Brandt
authors: Katheryn
authors: K
authors: Meek
authors: David B
authors: DB
authors: Roth
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; C511788:XRCC4 protein, mouse; C064658:RAG-1 protein