Germinal center (GC) B cells are among the fastest replicating cells in our body, dividing every 4–8 h. DNA replication errors are intrinsically toxic to cells. How GC B cells exert control over the DNA damage response while introducing mutations in their antibody genes is poorly understood. Here, we show that the DNA damage response regulator Checkpoint kinase 1 (CHK1) is essential for GC B cell survival. Remarkably, effective antibody-mediated immunity relies on optimal CHK1 dosage. Chemical CHK1 inhibition or loss of one Chk1 allele impairs the survival of class-switched cells and curbs the amplitude of antibody production. Mechanistically, active B cell receptor signaling wires the outcome of CHK1-inhibition towards BIM-dependent apoptosis, whereas T cell help favors temporary cell cycle arrest. Our results predict that therapeutic CHK1 inhibition in cancer patients may prove potent in killing B cell lymphoma and leukemia cells addicted to B cell receptor signaling, but will most likely dampen humoral immunity.
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We thank I. Gaggl and K. Rossi for expert technical assistance; M. Saurwein, N. Heinrich, and N. Schöpf for animal care; I. Lengenfelder and C. Rahm for administrative assistance; the present and former V.L. and A.V. lab members and E. Derudder for critical comments and suggestions; K. Rajewsky for Cg1-cre mice; A. Strasser for Bim− mice, T.W. Mak for Chk1F mice, M. Herold for providing an antibody against BCL2a1 (clone 6D6), and B. Weinberger for technical help with ELISPOT analysis. This work was supported by grants from the Austrian Science Fund (FWF) to AV (P 26856; I1298) and to NH-K (P 28694-B30), the Tyrolean Science Fund to VL (UNI-0404/1696) and the Austrian Cancer Aid to VL (KH15017). KS was supported by the FWF-funded Doctoral College “Molecular Cell Biology and Oncology” (W1101), and received a DOC PhD fellowship from the Austrian Academy of Sciences (ÖAW).