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PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency.


ABSTRACT: The serine/threonine phosphatase PP4 has been implicated in DNA damage repair and cell cycle regulation through its dephosphorylation of specific substrates. We previously showed that PP4 is required for mouse B cell development, germinal center (GC) formation and immunoglobulin (Ig) class switch recombination (CSR). Here, we investigate the mechanisms underlying this requirement and demonstrate that murine PP4-deficient B lymphocytes have a defect in cell proliferation. Strikingly, the DNA damage response pathway that involves ATM/p53 and is linked to cell cycle arrest and impaired cell survival is strongly induced in these mutant B cells. In response to LPS?+?IL-4, stimuli that trigger IgG1 production, these PP4-deficient B cells show inefficient phosphorylation of ATR, leading to reduced retention of ?H2AX-NBS1 complexes at sites of DNA damage, and compromised switching to IgG1. However, beyond the cell proliferation phase, conditional deletion of PP4 under the control of AID/cre completely restores normal IgG1 production in mutant B cell cultures. In vivo, co-deletion of PP4 and p53 by AID/cre partially rescues switching to IgG1 in B cells of mice immunized with TNP-KLH. Our findings establish that PP4 is indispensable for preventing DNA replication stress that could interfere with CSR, thereby promoting antibody switching during the humoral immune response.

SUBMITTER: Chen MY 

PROVIDER: S-EPMC6748143 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency.

Chen Ming-Yu MY   Hsu Wei-Chan WC   Hsu Shu-Ching SC   Yang Yu-Shao YS   Chuang Tsung-Hsien TH   Lin Wen-Jye WJ   Tan Tse-Hua TH   Su Yu-Wen YW  

Cell death and differentiation 20180920 7


The serine/threonine phosphatase PP4 has been implicated in DNA damage repair and cell cycle regulation through its dephosphorylation of specific substrates. We previously showed that PP4 is required for mouse B cell development, germinal center (GC) formation and immunoglobulin (Ig) class switch recombination (CSR). Here, we investigate the mechanisms underlying this requirement and demonstrate that murine PP4-deficient B lymphocytes have a defect in cell proliferation. Strikingly, the DNA dama  ...[more]

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