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

Cell Death and Differentiation
Ming-Yu ChenYu-Wen Su

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 γH2AX-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 ...Continue Reading

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Citations

Dec 31, 2020·Molecular Human Reproduction·F HanQ Y Sun
Feb 6, 2021·Molecular Human Reproduction·F HanQ Y Sun

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Methods Mentioned

BETA
FACS
flow cytometry
electrophoresis
confocal microscopy
nuclear translocation

Software Mentioned

MetaMorph
Image J
FACSDiva

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