title: RAG Represents a Widespread Threat to the Lymphocyte Genome.
abstract: The RAG1 endonuclease, together with its cofactor RAG2, is essential for V(D)J recombination but is a potent threat to genome stability. The sources of RAG1 mis-targeting and the mechanisms that have evolved to suppress it are poorly understood. Here, we report that RAG1 associates with chromatin at thousands of active promoters and enhancers in the genome of developing lymphocytes. The mouse and human genomes appear to have responded by reducing the abundance of "cryptic" recombination signals near RAG1 binding sites. This depletion operates specifically on the RSS heptamer, whereas nonamers are enriched at RAG1 binding sites. Reversing this RAG-driven depletion of cleavage sites by insertion of strong recombination signals creates an ectopic hub of RAG-mediated V(D)J recombination and chromosomal translocations. Our findings delineate rules governing RAG binding in the genome, identify areas at risk of RAG-mediated damage, and highlight the evolutionary struggle to accommodate programmed DNA damage in developing lymphocytes.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Teng
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Maman
authors.affiliation: Genomics and Immunity, NIAMS, Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Resch
authors.affiliation: Division of Biomedical Informatics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Box 9066, Dallas, TX 75390-9066, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Kim
authors.affiliation: Genomics and Immunity, NIAMS, Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.affiliation: Genomics and Immunity, NIAMS, Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Qian
authors.affiliation: Genomics and Immunity, NIAMS, Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kyong-Rim
authors.initials: KR
authors.lastname: Kieffer-Kwon
authors.affiliation: Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Malay
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Department of Immunology and Microbiology, College of Medicine, Xi'an Jiao Tong University, 76 Yan Ta West Road, Box 37, Xian, Shaanxi 710061, PRC.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Clark
authors.affiliation: Division of Biomedical Informatics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Box 9066, Dallas, TX 75390-9066, USA.
authors.forename: Lindsay G
authors.initials: LG
authors.lastname: Cowell
authors.affiliation: Genomics and Immunity, NIAMS, Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: casellar@mail.nih.gov.
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA; Howard Hughes Medical Institute, 295 Congress Avenue, New Haven, CT 06511, USA. Electronic address: david.schatz@yale.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D042822:Genomic Instability; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D014178:Translocation, Genetic; D060152:V(D)J Recombination
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D064007:Ataxia Telangiectasia Mutated Proteins