Cargando…

Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation

Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes initiated by activation-induced cytidine deaminase. Here, we have studied the role of ataxia telangiectasia and Rad3-related protein (ATR) in CSR by analyzing the recombinational junctions, resulti...

Descripción completa

Detalles Bibliográficos
Autores principales: Pan-Hammarström, Qiang, Lähdesmäki, Aleksi, Zhao, Yaofeng, Du, Likun, Zhao, Zhihui, Wen, Sicheng, Ruiz-Perez, Victor L., Dunn-Walters, Deborah K., Goodship, Judith A., Hammarström, Lennart
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118080/
https://www.ncbi.nlm.nih.gov/pubmed/16390936
http://dx.doi.org/10.1084/jem.20050595
_version_ 1782140943483273216
author Pan-Hammarström, Qiang
Lähdesmäki, Aleksi
Zhao, Yaofeng
Du, Likun
Zhao, Zhihui
Wen, Sicheng
Ruiz-Perez, Victor L.
Dunn-Walters, Deborah K.
Goodship, Judith A.
Hammarström, Lennart
author_facet Pan-Hammarström, Qiang
Lähdesmäki, Aleksi
Zhao, Yaofeng
Du, Likun
Zhao, Zhihui
Wen, Sicheng
Ruiz-Perez, Victor L.
Dunn-Walters, Deborah K.
Goodship, Judith A.
Hammarström, Lennart
author_sort Pan-Hammarström, Qiang
collection PubMed
description Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes initiated by activation-induced cytidine deaminase. Here, we have studied the role of ataxia telangiectasia and Rad3-related protein (ATR) in CSR by analyzing the recombinational junctions, resulting from in vivo switching, in cells from patients with mutations in the ATR gene. The proportion of cells that have switched to immunoglobulin (Ig)A and IgG in the peripheral blood seems to be normal in ATR-deficient (ATRD) patients and the recombined S regions show a normal “blunt end-joining,” but impaired end joining with partially complementary (1–3 bp) DNA ends. There was also an increased usage of microhomology at the μ-α switch junctions, but only up to 9 bp, suggesting that the end-joining pathway requiring longer microhomologies (≥10 bp) may be ATR dependent. The SHM pattern in the Ig variable heavy chain genes is altered, with fewer mutations occurring at A and more mutations at T residues and thus a loss of strand bias in targeting A/T pairs within certain hotspots. These data suggest that the role of ATR is partially overlapping with that of ataxia telangiectasia–mutated protein, but that the former is also endowed with unique functional properties in the repair processes during CSR and SHM.
format Text
id pubmed-2118080
institution National Center for Biotechnology Information
language English
publishDate 2006
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-21180802007-12-13 Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation Pan-Hammarström, Qiang Lähdesmäki, Aleksi Zhao, Yaofeng Du, Likun Zhao, Zhihui Wen, Sicheng Ruiz-Perez, Victor L. Dunn-Walters, Deborah K. Goodship, Judith A. Hammarström, Lennart J Exp Med Articles Class switch recombination (CSR) and somatic hypermutation (SHM) are mechanistically related processes initiated by activation-induced cytidine deaminase. Here, we have studied the role of ataxia telangiectasia and Rad3-related protein (ATR) in CSR by analyzing the recombinational junctions, resulting from in vivo switching, in cells from patients with mutations in the ATR gene. The proportion of cells that have switched to immunoglobulin (Ig)A and IgG in the peripheral blood seems to be normal in ATR-deficient (ATRD) patients and the recombined S regions show a normal “blunt end-joining,” but impaired end joining with partially complementary (1–3 bp) DNA ends. There was also an increased usage of microhomology at the μ-α switch junctions, but only up to 9 bp, suggesting that the end-joining pathway requiring longer microhomologies (≥10 bp) may be ATR dependent. The SHM pattern in the Ig variable heavy chain genes is altered, with fewer mutations occurring at A and more mutations at T residues and thus a loss of strand bias in targeting A/T pairs within certain hotspots. These data suggest that the role of ATR is partially overlapping with that of ataxia telangiectasia–mutated protein, but that the former is also endowed with unique functional properties in the repair processes during CSR and SHM. The Rockefeller University Press 2006-01-23 /pmc/articles/PMC2118080/ /pubmed/16390936 http://dx.doi.org/10.1084/jem.20050595 Text en Copyright © 2006, The Rockefeller University Press 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 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Articles
Pan-Hammarström, Qiang
Lähdesmäki, Aleksi
Zhao, Yaofeng
Du, Likun
Zhao, Zhihui
Wen, Sicheng
Ruiz-Perez, Victor L.
Dunn-Walters, Deborah K.
Goodship, Judith A.
Hammarström, Lennart
Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation
title Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation
title_full Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation
title_fullStr Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation
title_full_unstemmed Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation
title_short Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation
title_sort disparate roles of atr and atm in immunoglobulin class switch recombination and somatic hypermutation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118080/
https://www.ncbi.nlm.nih.gov/pubmed/16390936
http://dx.doi.org/10.1084/jem.20050595
work_keys_str_mv AT panhammarstromqiang disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT lahdesmakialeksi disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT zhaoyaofeng disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT dulikun disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT zhaozhihui disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT wensicheng disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT ruizperezvictorl disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT dunnwaltersdeborahk disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT goodshipjuditha disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation
AT hammarstromlennart disparaterolesofatrandatminimmunoglobulinclassswitchrecombinationandsomatichypermutation