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

Jeffrey J. Bednarski, Ruchi Pandey, Emily Schulte, Lynn S. White, Bo Ruei Chen, Gabriel J. Sandoval, Masako Kohyama, Malay Haldar, Andrew Nickless, Amanda Trott, Genhong Cheng, Kenneth M. Murphy, Craig H. Bassing, Jacqueline E. Payton, Barry P. Sleckman

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)209-223
Number of pages15
JournalJournal of Experimental Medicine
Volume213
Issue number2
DOIs
StatePublished - Feb 8 2016

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