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

Authors :
Bednarski, Jeffrey J.
Pandey, Ruchi
Schulte, Emily
White, Lynn S.
Chen, Bo-Ruei
Sandoval, Gabriel J.
Kohyama, Masako
Haldar, Malay
Nickless, Andrew
Trott, Amanda
Cheng, Genhong
Murphy, Kenneth M.
Bassing, Craig H.
Payton, Jacqueline E.
Sleckman, Barry P.
Source :
The Journal of Experimental Medicine; February 2016, Vol. 213 Issue: 2 p209-223, 15p
Publication Year :
2016

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.

Details

Language :
English
ISSN :
00221007 and 15409538
Volume :
213
Issue :
2
Database :
Supplemental Index
Journal :
The Journal of Experimental Medicine
Publication Type :
Periodical
Accession number :
ejs38027869
Full Text :
https://doi.org/10.1084/jem.20151048