RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals
Year: 2016
Type: article
Abstract: 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-κB2-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.
DOI: 10.1084/jem.20151048
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Alex's Lemonade Stand Foundation for Childhood Cancer, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences, Hyundai Hope On Wheels, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Training Program in Developmental Hematology, G2529364759, G3875974780, ATM Function During V(D)J Recombination, G4374913468, The V(D)J Recombination Reaction and ITS impact on Lymphocyte Development, INTEGRATION OF DNA DAMAGE RESPONSES WITH IMMUNE DEVELOPMENT AND FUNCTION, Washington University Institute of Clinical and Translational Sciences, ACTIVATION OF CELLULAR SIGNALING PATHWAYS BY DNA DOUBLE STRAND BREAKS, METABOLIC CONTROL OF TISSUE SPECIFIC MACROPHAGE DIFFERENTIATION, DNA Double Strand Break Mediated Feedback Inhibition of V(D)J Recombination, G9000115080, G9000319192, Molecular Oncology Training Grant, Cancer Center Support Grant
OpenAlex ID: W2267033810