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.

ORGANISM(S): Mus musculus

PROVIDER: GSE67854 | GEO | 2016/01/13

SECONDARY ACCESSION(S): PRJNA281075

REPOSITORIES: GEO