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SSB1/SSB2 proteins safeguard B-cell development by protecting the genomes of B-cell precursors

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Title: SSB1/SSB2 proteins safeguard B-cell development by protecting the genomes of B-cell precursors
Authors: Pfeifer, M
Brem, R
Lippert, T
Boulianne, B
Ho, HN
Robinson, M
Stebbing, J
Feldhahn, N
Item Type: Journal Article
Abstract: Induction of programmed DNA damage and its recognition and repair are fundamental for B cell development. The ssDNA-binding protein SSB1 has been described in human cells as essential for the recognition and repair of DNA damage. To study its relevance for B cells, we recently developed Ssb1−/− and conditional Ssb1−/− mice. Although SSB1 loss did not affect B cell development, Ssb1−/− cells exhibited compensatory expression of its homolog SSB2. We have now generated Ssb2−/− mice and show in this study that SSB2 is also dispensable for B cell development and DNA damage response activation. In contrast to the single loss of Ssb1 or Ssb2, however, combined SSB1/2 deficiency caused a defect in early B cell development. We relate this to the sensitivity of B cell precursors as mature B cells largely tolerated their loss. Toxicity of combined genetic SSB1/2 loss can be rescued by ectopic expression of either SSB1 or SSB2, mimicked by expression of SSB1 ssDNA-binding mutants, and attenuated by BCL2-mediated suppression of apoptosis. SSB1/2 loss in B cell precursors further caused increased exposure of ssDNA associated with disruption of genome fragile sites, inefficient cell cycle progression, and increased DNA damage if apoptosis is suppressed. As such, our results establish SSB1/2 as safeguards of B cell development and unveil their differential requirement in immature and mature B lymphocytes.
Issue Date: 15-Jun-2019
Date of Acceptance: 16-Apr-2019
URI: http://hdl.handle.net/10044/1/70231
DOI: https://dx.doi.org/10.4049/jimmunol.1801618
ISSN: 1550-6606
Publisher: American Association of Immunologists
Start Page: 3423
End Page: 3433
Journal / Book Title: Journal of Immunology
Volume: 202
Issue: 12
Copyright Statement: © 2019 The Authors This article is distributed under the terms of the CC BY 4.0 Unported license (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Action Against Cancer
Bloodwise
Bloodwise
Leuka
Commission of the European Communities
Funder's Grant Number: N/A
13016
13016
P47415
630911
Keywords: Immunology
1107 Immunology
Publication Status: Published
Online Publication Date: 2019-06-03
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine



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