Cargando…

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

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) c...

Descripción completa

Detalles Bibliográficos
Autores principales: Bednarski, Jeffrey J., Pandey, Ruchi, Schulte, Emily, White, Lynn S., Chen, Bo-Ruei, Sandoval, Gabriel J., Kohyama, Masako, Haldar, Malay, Nickless, Andrew, Trott, Amanda, Cheng, Genhong, Murphy, Kenneth M., Bassing, Craig H., Payton, Jacqueline E., Sleckman, Barry P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749927/
https://www.ncbi.nlm.nih.gov/pubmed/26834154
http://dx.doi.org/10.1084/jem.20151048
_version_ 1782415341440204800
author Bednarski, Jeffrey J.
Pandey, Ruchi
Schulte, Emily
White, Lynn S.
Chen, Bo-Ruei
Sandoval, Gabriel J.
Kohyama, Masako
Haldar, Malay
Nickless, Andrew
Trott, Amanda
Cheng, Genhong
Murphy, Kenneth M.
Bassing, Craig H.
Payton, Jacqueline E.
Sleckman, Barry P.
author_facet Bednarski, Jeffrey J.
Pandey, Ruchi
Schulte, Emily
White, Lynn S.
Chen, Bo-Ruei
Sandoval, Gabriel J.
Kohyama, Masako
Haldar, Malay
Nickless, Andrew
Trott, Amanda
Cheng, Genhong
Murphy, Kenneth M.
Bassing, Craig H.
Payton, Jacqueline E.
Sleckman, Barry P.
author_sort Bednarski, Jeffrey J.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4749927
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-47499272016-08-08 RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals Bednarski, Jeffrey J. Pandey, Ruchi Schulte, Emily White, Lynn S. Chen, Bo-Ruei Sandoval, Gabriel J. Kohyama, Masako Haldar, Malay Nickless, Andrew Trott, Amanda Cheng, Genhong Murphy, Kenneth M. Bassing, Craig H. Payton, Jacqueline E. Sleckman, Barry P. J Exp Med Research Articles 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. The Rockefeller University Press 2016-02-08 /pmc/articles/PMC4749927/ /pubmed/26834154 http://dx.doi.org/10.1084/jem.20151048 Text en © 2016 Bednarski et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Bednarski, Jeffrey J.
Pandey, Ruchi
Schulte, Emily
White, Lynn S.
Chen, Bo-Ruei
Sandoval, Gabriel J.
Kohyama, Masako
Haldar, Malay
Nickless, Andrew
Trott, Amanda
Cheng, Genhong
Murphy, Kenneth M.
Bassing, Craig H.
Payton, Jacqueline E.
Sleckman, Barry P.
RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals
title RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals
title_full RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals
title_fullStr RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals
title_full_unstemmed RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals
title_short RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals
title_sort rag-mediated dna double-strand breaks activate a cell type–specific checkpoint to inhibit pre–b cell receptor signals
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749927/
https://www.ncbi.nlm.nih.gov/pubmed/26834154
http://dx.doi.org/10.1084/jem.20151048
work_keys_str_mv AT bednarskijeffreyj ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT pandeyruchi ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT schulteemily ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT whitelynns ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT chenboruei ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT sandovalgabrielj ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT kohyamamasako ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT haldarmalay ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT nicklessandrew ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT trottamanda ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT chenggenhong ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT murphykennethm ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT bassingcraigh ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT paytonjacquelinee ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals
AT sleckmanbarryp ragmediateddnadoublestrandbreaksactivateacelltypespecificcheckpointtoinhibitprebcellreceptorsignals