PMID- 26834154 OWN - NLM STAT- MEDLINE DCOM- 20160815 LR - 20231213 IS - 1540-9538 (Electronic) IS - 0022-1007 (Print) IS - 0022-1007 (Linking) VI - 213 IP - 2 DP - 2016 Feb 8 TI - RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals. PG - 209-23 LID - 10.1084/jem.20151048 [doi] AB - DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre-B cell receptor (pre-BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre-BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre-B cells. Here, we show that RAG DSBs inhibit pre-BCR signals through the ATM- and NF-kappaB2-dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor, resulting in suppression of pre-BCR signaling. This regulatory circuit prevents the pre-BCR from inducing additional Igl chain gene rearrangements and driving pre-B cells with RAG DSBs into cycle. We propose that pre-B cells toggle between pre-BCR signals and a RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes. CI - (c) 2016 Bednarski et al. FAU - Bednarski, Jeffrey J AU - Bednarski JJ AD - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110. FAU - Pandey, Ruchi AU - Pandey R AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Schulte, Emily AU - Schulte E AD - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110. FAU - White, Lynn S AU - White LS AD - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110. FAU - Chen, Bo-Ruei AU - Chen BR AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Sandoval, Gabriel J AU - Sandoval GJ AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Kohyama, Masako AU - Kohyama M AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Haldar, Malay AU - Haldar M AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Nickless, Andrew AU - Nickless A AD - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110. FAU - Trott, Amanda AU - Trott A AD - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110. FAU - Cheng, Genhong AU - Cheng G AD - Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095. FAU - Murphy, Kenneth M AU - Murphy KM AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Bassing, Craig H AU - Bassing CH AD - Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104. FAU - Payton, Jacqueline E AU - Payton JE AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. FAU - Sleckman, Barry P AU - Sleckman BP AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 bas2022@med.cornell.edu. LA - eng GR - T32 CA113275/CA/NCI NIH HHS/United States GR - R01 AI112621/AI/NIAID NIH HHS/United States GR - K08AI106953/AI/NIAID NIH HHS/United States GR - K08 AI102946/AI/NIAID NIH HHS/United States GR - AI47829/AI/NIAID NIH HHS/United States GR - R01AI112621/AI/NIAID NIH HHS/United States GR - T32 HD007499/HD/NICHD NIH HHS/United States GR - K08AI102946-01/AI/NIAID NIH HHS/United States GR - K08 AI106953/AI/NIAID NIH HHS/United States GR - P30 CA091842/CA/NCI NIH HHS/United States GR - UL1 TR000448/TR/NCATS NIH HHS/United States GR - R01 AI074953/AI/NIAID NIH HHS/United States GR - R01 CA136470/CA/NCI NIH HHS/United States GR - CA136470/CA/NCI NIH HHS/United States GR - AI074953/AI/NIAID NIH HHS/United States GR - R01 AI047829/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160201 PL - United States TA - J Exp Med JT - The Journal of experimental medicine JID - 2985109R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (B cell linker protein) RN - 0 (DNA-Binding Proteins) RN - 0 (Homeodomain Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (NF-kappa B p52 Subunit) RN - 0 (Nfkb2 protein, mouse) RN - 0 (Pre-B Cell Receptors) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Spic protein, mouse) RN - 0 (Trans-Activators) RN - 0 (proto-oncogene protein Spi-1) RN - 128559-51-3 (RAG-1 protein) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (Syk Kinase) RN - EC 2.7.10.2 (Syk protein, mouse) RN - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2.7.11.1 (Atm protein, mouse) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Adaptor Proteins, Signal Transducing/metabolism MH - Animals MH - Ataxia Telangiectasia Mutated Proteins/deficiency/genetics/metabolism MH - Cell Cycle Checkpoints/immunology MH - Cell Proliferation MH - *DNA Breaks, Double-Stranded MH - DNA-Binding Proteins/deficiency/genetics/metabolism MH - Gene Rearrangement, B-Lymphocyte, Light Chain MH - Homeodomain Proteins/genetics/*metabolism MH - Intracellular Signaling Peptides and Proteins/metabolism MH - Mice MH - Mice, Knockout MH - Mice, Transgenic MH - NF-kappa B p52 Subunit/deficiency/genetics/metabolism MH - Pre-B Cell Receptors/*metabolism MH - Precursor Cells, B-Lymphoid/cytology/*immunology/*metabolism MH - Protein Serine-Threonine Kinases/metabolism MH - Protein-Tyrosine Kinases/metabolism MH - Proto-Oncogene Proteins/metabolism MH - Signal Transduction/immunology MH - Syk Kinase MH - Trans-Activators/metabolism MH - NF-kappaB-Inducing Kinase PMC - PMC4749927 EDAT- 2016/02/03 06:00 MHDA- 2016/08/16 06:00 PMCR- 2016/08/08 CRDT- 2016/02/03 06:00 PHST- 2015/06/24 00:00 [received] PHST- 2015/12/03 00:00 [accepted] PHST- 2016/02/03 06:00 [entrez] PHST- 2016/02/03 06:00 [pubmed] PHST- 2016/08/16 06:00 [medline] PHST- 2016/08/08 00:00 [pmc-release] AID - jem.20151048 [pii] AID - 20151048 [pii] AID - 10.1084/jem.20151048 [doi] PST - ppublish SO - J Exp Med. 2016 Feb 8;213(2):209-23. doi: 10.1084/jem.20151048. Epub 2016 Feb 1.