RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells through Activation of a SPIC-BCLAF1 Complex

Cell Rep. 2019 Oct 22;29(4):829-843.e5. doi: 10.1016/j.celrep.2019.09.026.


Early B cell development is regulated by stage-specific transcription factors. PU.1, an ETS-family transcription factor, is essential for coordination of early B cell maturation and immunoglobulin gene (Ig) rearrangement. Here we show that RAG DNA double-strand breaks (DSBs) generated during Ig light chain gene (Igl) rearrangement in pre-B cells induce global changes in PU.1 chromatin binding. RAG DSBs activate a SPIC/BCLAF1 transcription factor complex that displaces PU.1 throughout the genome and regulates broad transcriptional changes. SPIC recruits BCLAF1 to gene-regulatory elements that control expression of key B cell developmental genes. The SPIC/BCLAF1 complex suppresses expression of the SYK tyrosine kinase and enforces the transition from large to small pre-B cells. These studies reveal that RAG DSBs direct genome-wide changes in ETS transcription factor activity to promote early B cell development.

Keywords: B cell development; BCLAF1 transcription factor; DNA damage response; PU.1 transcription factor; RAG; SPIC transcription factor; pre-B cells.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism*
  • Cell Differentiation*
  • Cells, Cultured
  • Chromatin / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA-Binding Proteins / metabolism*
  • Female
  • Homeodomain Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Proto-Oncogene Proteins / metabolism*
  • Repressor Proteins / metabolism*
  • Syk Kinase / metabolism
  • Trans-Activators / metabolism*


  • Bclaf1 protein, mouse
  • Chromatin
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Proto-Oncogene Proteins
  • Rag2 protein, mouse
  • Repressor Proteins
  • Spic protein, mouse
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • RAG-1 protein
  • Syk Kinase