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

J Exp Med. 2016 Feb 8;213(2):209-23. doi: 10.1084/jem.20151048. Epub 2016 Feb 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / deficiency
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Cycle Checkpoints / immunology
  • Cell Proliferation
  • DNA Breaks, Double-Stranded*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Rearrangement, B-Lymphocyte, Light Chain
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NF-kappa B p52 Subunit / deficiency
  • NF-kappa B p52 Subunit / genetics
  • NF-kappa B p52 Subunit / metabolism
  • NF-kappaB-Inducing Kinase
  • Pre-B Cell Receptors / metabolism*
  • Precursor Cells, B-Lymphoid / cytology
  • Precursor Cells, B-Lymphoid / immunology*
  • Precursor Cells, B-Lymphoid / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / immunology
  • Syk Kinase
  • Trans-Activators / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B p52 Subunit
  • Nfkb2 protein, mouse
  • Pre-B Cell Receptors
  • Proto-Oncogene Proteins
  • Spic protein, mouse
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • RAG-1 protein
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases