Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD+. Hence, mice lacking PARP-1 or PARP-2 show DNA perturbations ranging from altered DNA integrity to impaired DNA repair. These effects stem from the central role that PARP-1 and PARP-2 have on the cellular response to DNA damage. Failure to mount a proper response culminates in cell death. Accordingly, PARP inhibitors are emerging as promising drugs in cancer therapy. However, the full impact of these inhibitors on immunity, including B-cell antibody production, remains elusive. Given that mice carrying dual PARP-1 and PARP-2 deficiency develop early embryonic lethality, we crossed PARP-1-deficient mice with mice carrying a B-cell-conditional PARP-2 gene deletion. We found that the resulting dually PARP-1 and PARP-2-deficient mice had perturbed bone-marrow B-cell development as well as profound peripheral depletion of transitional and follicular but not marginal zone B-cells. Of note, bone-marrow B-cell progenitors and peripheral mature B-cells were conserved in mice carrying either PARP-1 or PARP-2 deficiency. In dually PARP-1 and PARP-2-deficient mice, B-cell lymphopenia was associated with increased DNA damage and accentuated death in actively proliferating B-cells. Moreover, dual PARP-1 and PARP-2 deficiency impaired antibody responses to T-independent carbohydrate but not to T-dependent protein antigens. Notwithstanding the pivotal role of PARP-1 and PARP-2 in DNA repair, combined PARP-1 and PARP-2 deficiency did not perturb the DNA-editing processes required for the generation of a protective antibody repertoire, including Ig V(D)J gene recombination and IgM-to-IgG class switching. These findings provide key information as to the potential impact of PARP inhibitors on humoral immunity, which will facilitate the development of safer PARP-targeting regimens against cancer.
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Conflict of interest
The authors declare that they have no conflict of interest.
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Edited by A. Villunger
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We thank P. Moreno and M. Juan for assistance with mice. The Deriano lab members for help with pro-B-cell lines experiments. O. Fornes for cell sorting and flow cytometry assistance. The Yélamos’s lab is funded by the Spanish Ministerio de Economía, Industria y Competitividad (grant SAF2017-83565-R) and The Fundación Científica de la Asociación Española Contra el Cáncer (AECC). The Deriano’s lab is funded by the Institut Pasteur, the Institut National du Cancer (# PLBIO16-181) and the European Research Council under the ERC (starting grant agreement #310917). The Dantzer’s lab is supported by LABEX ANR-10-LABX-0034_Medalis, Strasbourg University, CNRS. The Cerutti’s lab is supported by the European Research Council (European Advanced Grant ERC-2011-ADG-20110310) and by the Spanish Ministerio de Economía, Industria y Competitividad (grant SAF2014-52483-R). MAG-C is supported by CONACyT.