RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells Through Activation of a SPIC-BCLAF1 Complex
Year: 2019
Type: article
Abstract: Early B cell development is regulated by stage-specific transcription factors. PU.1, an ETS-family transcription factor, is essential for coordination of early B cell maturation and immunoglobulin gene (Ig) rearrangement. Here we show that RAG DNA double-strand breaks (DSBs) generated during Ig light chain gene (Igl) rearrangement in pre-B cells induce global changes in PU.1 chromatin binding. RAG DSBs activate a SPIC/BCLAF1 transcription factor complex that displaces PU.1 throughout the genome and regulates broad transcriptional changes. SPIC recruits BCLAF1 to gene-regulatory elements that control expression of key B cell developmental genes. The SPIC/BCLAF1 complex suppresses expression of the SYK tyrosine kinase and enforces the transition from large to small pre-B cells. These studies reveal that RAG DSBs direct genome-wide changes in ETS transcription factor activity to promote early B cell development.
Source: Cell Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: American Cancer Society, American Society of Hematology, Alex's Lemonade Stand Foundation for Childhood Cancer, Regeneron Pharmaceuticals, Alvin J. Siteman Cancer Center, National Institutes of Health, Washington University School of Medicine in St. Louis, National Human Genome Research Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences
Awards: Production of Targeted Null Mutations for 10,000 Genes in C57BL/6 ES Cells, A SIGNALING PATHWAY SPECIFIC FOR ALKYLATION DAMAGE, Damaged RNA as a mediator of alkylation responses, INTEGRATION OF DNA DAMAGE RESPONSES WITH IMMUNE DEVELOPMENT AND FUNCTION, Washington University Institute of Clinical and Translational Sciences, SEQUENCE-SPECIFIC CHROMATIN MODIFIERS; NOVEL PROTEIN THERAPEUTICS FOR B CELL LYMPHOMA, Role of DNA Damage Responses in Immune Development and Function, High-throughput targeted mutagenesis of mouse stem cell lines, G9000115080, G9000319192, Structural Cell Biology of DNA Repair Machines, Washington University Institute of Clinical and Translational Sciences, Washington University Institute of Clinical and Translational Sciences (KL2), Cancer Center Support Grant
OpenAlex ID: W2981824828