| First Author | Chen MY | Year | 2019 |
| Journal | Cell Death Differ | Volume | 26 |
| Issue | 7 | Pages | 1221-1234 |
| PubMed ID | 30237510 | Mgi Jnum | J:279440 |
| Mgi Id | MGI:6360770 | Doi | 10.1038/s41418-018-0199-z |
| Citation | Chen MY, et al. (2019) PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency. Cell Death Differ 26(7):1221-1234 |
| abstractText | 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 gammaH2AX-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. |
