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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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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 |
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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 |
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