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: Barbara Corneo, Rebecca L Wendland, Ludovic Deriano, Xiaoping Cui, Isaac A Klein, Serre-Yu Wong, Suzzette Arnal, Abigail J Holub, Geoffrey R Weller, Bette A Pancake, Sundeep Shah, Vicky L Brandt, Katheryn Meek, David B Roth
• Journal: Nature (Nature) Vol. 449 Issue 7161 Pg. 483-6 (Sep 27 2007) ISSN: 1476-4687 [Electronic] England
• PMID: 17898768 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Homeodomain Proteins
• Rag2 protein, mouse
• XRCC4 protein, mouse
• RAG-1 protein

Topics

• Animals
• DNA-Binding Proteins (chemistry, deficiency, genetics, metabolism)
• Homeodomain Proteins (chemistry, genetics, metabolism)
• Mice
• Models, Genetic
• Mutation (genetics)
• Recombination, Genetic (genetics)