Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 2, Pages 209-223Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151048
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Funding
- National Institutes of Health [CA136470, AI074953, AI47829, K08AI102946-01, K08AI106953, R01AI112621]
- Hyundai Hope on Wheels Scholar Award
- Alex's Lemonade Stand Foundation Award
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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-kappa B2-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.
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