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

63 Pages Posted: 1 Apr 2019 Sneak Peek Status: Review Complete

See all articles by Deepti Soodgupta

Deepti Soodgupta

Washington University in St. Louis - Department of Pediatrics

Lynn S. White

Washington University in St. Louis - Department of Pediatrics

Wei Yang

Washington University in St. Louis - Department of Genetics

Rachel Johnston

Washington University in St. Louis - Department of Pediatrics

Nima Mosammaparast

Washington University in St. Louis - Department of Pathology and Immunology

Jacqueline E. Payton

Washington University in St. Louis - Department of Pathology and Immunology

Jeffrey Bednarski

Washington University in St. Louis - Department of Pediatrics

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Abstract

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 uniquely 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: Pre-B cells, DNA damage response, B cell development, RAG, PU.1 transcription factor, SPIC transcription factor, BCLAF1 transcription factor

Suggested Citation

Soodgupta, Deepti and White, Lynn S. and Yang, Wei and Johnston, Rachel and Mosammaparast, Nima and Payton, Jacqueline E. and Bednarski, Jeffrey, RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells Through Activation of a SPIC-BCLAF1 Complex (March 29, 2019). Available at SSRN: https://ssrn.com/abstract=3362390 or http://dx.doi.org/10.2139/ssrn.3362390
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Deepti Soodgupta

Washington University in St. Louis - Department of Pediatrics

660 South Euclid Avenue
Campus Box 8208
St. Louis, MO 63130
United States

Lynn S. White

Washington University in St. Louis - Department of Pediatrics

660 South Euclid Avenue
Campus Box 8208
St. Louis, MO 63130
United States

Wei Yang

Washington University in St. Louis - Department of Genetics

4515 McKinley Ave
St. Louis, WA 63110
United States

Rachel Johnston

Washington University in St. Louis - Department of Pediatrics

660 South Euclid Avenue
Campus Box 8208
St. Louis, MO 63130
United States

Nima Mosammaparast

Washington University in St. Louis - Department of Pathology and Immunology

One Brookings Drive
Campus Box 1208
Saint Louis, MO 63130-4899
United States

Jacqueline E. Payton

Washington University in St. Louis - Department of Pathology and Immunology

One Brookings Drive
Campus Box 1208
Saint Louis, MO 63130-4899
United States

Jeffrey Bednarski (Contact Author)

Washington University in St. Louis - Department of Pediatrics ( email )

660 South Euclid Avenue
Campus Box 8208
St. Louis, MO 63130
United States

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