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

The Journal of Experimental Medicine
Jeffrey J BednarskiBarry P Sleckman

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.

References

Jan 1, 1992·Molecular and Cellular Biology·J M PongubalaM L Atchison
Apr 3, 1999·The Journal of Biological Chemistry·M BemarkT Leanderson
Jun 3, 2000·Annual Review of Immunology·S D FugmannD G Schatz
Feb 27, 2001·Science·R CasellasM C Nussenzweig
Nov 19, 2002·Nature Immunology·Alexandra FlemmingHassan Jumaa
Mar 4, 2003·Nature Reviews. Cancer·Yosef Shiloh
Dec 23, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Brock L Schweitzer, Rodney P DeKoter
May 19, 2004·Proceedings of the National Academy of Sciences of the United States of America·Brian ZarnegarGenhong Cheng
Nov 30, 2006·The Journal of Experimental Medicine·Thomas WossningHassan Jumaa
May 10, 2008·European Journal of Immunology·Farnaz Fallah-AraniVictor L J Tybulewicz
Sep 17, 2008·Cellular Signalling·John C SitkoNicholas A Cacalano
Sep 19, 2008·Nature Immunology·Tracy S P HengUNKNOWN Immunological Genome Project Consortium
Feb 26, 2009·Nature Reviews. Immunology·Sebastian HerzogHassan Jumaa
Dec 28, 2011·The Journal of Experimental Medicine·Jeffrey J BednarskiBarry P Sleckman
Jan 10, 2012·Annual Review of Immunology·Beth A Helmink, Barry P Sleckman
Feb 4, 2012·Genes & Development·Matthew S Hayden, Sankar Ghosh
Mar 17, 2012·Seminars in Immunology·Steven A Corfe, Christopher J Paige
Mar 23, 2012·Immunological Reviews·Shao-Cong Sun
Sep 8, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Li S XuRodney P DeKoter
Feb 6, 2013·The Journal of Experimental Medicine·Natalie C SteinelCraig H Bassing

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Citations

Feb 10, 2016·The Journal of Experimental Medicine·Stephen Desiderio
Apr 4, 2017·Nature Reviews. Immunology·David Nemazee
Nov 20, 2016·Mechanisms of Ageing and Development·Chloé Lescale, Ludovic Deriano
Feb 19, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Megan R FisherCraig H Bassing
Apr 13, 2019·Immunological Reviews·Sandra Zehentmeier, João P Pereira
Dec 21, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Huikun ZhangYongjie Ma
Aug 31, 2018·The Journal of Experimental Medicine·Chris FistonichJoão P Pereira
Sep 27, 2018·Nature Communications·Malay MandalMarcus R Clark
Jan 25, 2019·Scientific Reports·Xiaoling LiuRenxi Wang
Feb 9, 2017·Frontiers in Immunology·Md Zahidul AlamMalay Haldar
Feb 20, 2019·Nature Reviews. Immunology·Jeffrey J Bednarski, Barry P Sleckman

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Methods Mentioned

BETA
nuclear translocation
transfection
Flow Cytometry
immunoprecipitation
electrophoresis
PCR

Software Mentioned

Partek Genomics Suite
GraphPad
ImmGen
Prism

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