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

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

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Cite this paper

@inproceedings{Bednarski2016RAGmediatedDD, title={RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals}, author={Jeffrey J. Bednarski and Ruchi Pandey and Emily Schulte and Lynn S. White and Bo-Ruei Chen and Gabriel J. Sandoval and Masako Kohyama and Malay Haldar and Andrew Nickless and Amanda Trott and Genhong Cheng and Kenneth M Murphy and Craig H. Bassing and Jacqueline E Payton and Barry P Sleckman}, booktitle={The Journal of experimental medicine}, year={2016} }