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Cohesin associated proteins NIPBL and SMC1A are involved in V(D)J recombination and somatic hypermutation in human B-cells

Björkman, Andrea, Du, Likun, van der Burg, Mirjam, Borck, Guntram, Pié, Juan, Ström, Lena, de Villartay, Jean-Pierre, Kipling, David, Dunn-Walters, Deborah and Pan-Hammarström, Qiang (2017) Cohesin associated proteins NIPBL and SMC1A are involved in V(D)J recombination and somatic hypermutation in human B-cells Journal of Allergy and Clinical Immunology.

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Cohesin associated proteins NIPBL and SMC1A are involved in V(D)J recombination and somatic hypermutation in human B-cells.docx - Accepted version Manuscript
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Abstract

The combinatorial assembly of variable (V), diversity (D) and joining (J) genes through long-range recombination at the immunoglobulin (Ig) gene loci is a highly regulated, tissue- and stage-specific process. Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder caused by mutations in genes of the cohesin pathway. Apart from its role during sister chromatid cohesion, cohesin has been implicated in DNA repair, transcriptional regulation and chromatin conformational changes. These processes are also important for V(D)J recombination. Here, we observed that the recombination efficiency is reduced in NIPBL deficient cells, at both coding and signal joints. Furthermore, using a high throughput sequencing method, we observed a reduced diversity of IG heavy (H) chain repertoires and a preferential usage of proximal IGHV genes in CdLS patient with mutations in NIPBL or SMC1A. Moreover, the frequency of mutations in the IGHV regions was markedly reduced in these cells, and the C residues in the bottom strand was less mutated. Our results thus suggest that the cohesin-associated proteins NIPBL and SMC1A are involved in regulation of both V(D)J recombination and somatic hypermutation, probably through regulation of locus contraction, transcription and AID targeting.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Björkman, AndreaUNSPECIFIEDUNSPECIFIED
Du, LikunUNSPECIFIEDUNSPECIFIED
van der Burg, MirjamUNSPECIFIEDUNSPECIFIED
Borck, GuntramUNSPECIFIEDUNSPECIFIED
Pié, JuanUNSPECIFIEDUNSPECIFIED
Ström, LenaUNSPECIFIEDUNSPECIFIED
de Villartay, Jean-PierreUNSPECIFIEDUNSPECIFIED
Kipling, DavidUNSPECIFIEDUNSPECIFIED
Dunn-Walters, Deborahd.dunn-walters@surrey.ac.ukUNSPECIFIED
Pan-Hammarström, QiangUNSPECIFIEDUNSPECIFIED
Date : 2017
Copyright Disclaimer : © 2017 Elsevier Ltd. All rights reserved.
Depositing User : Clive Harris
Date Deposited : 05 Jul 2017 07:26
Last Modified : 05 Jul 2017 07:26
URI: http://epubs.surrey.ac.uk/id/eprint/841534

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