Dataset Information


RAG-mediated DNA double strand breaks activate a cell-type-specific checkpoint to inhibit pre-B cell receptor signals

ABSTRACT: Pre-B cell receptor (pre-BCR) signals initiate immunoglobulin light (Igl) chain gene assembly leading to RAG-mediated DNA double-strand breaks (DSBs). These signals also promote 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 to prevent 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 this RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes. Overall design: Three independent IL-7 cultures for each genotype (Rag1-/-:μIgH:Bcl2, Art-/-:μIgH:Bcl2 and Art-/-:Nfkb2-/-:μIgH:Bcl2) were withdrawn from IL-7 for 2 days. RNA was isolated using RNeasy (Qiagen). Gene expression profiling was performed using Illumina MouseRef-8 expression microarrays.

INSTRUMENT(S): Illumina MouseRef-8 v2.0 expression beadchip

ORGANISM(S): Mus musculus  

SUBMITTER: Jeffrey J Bednarski  




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