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Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function

Abstract

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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Acknowledgements

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.

Author information

MAG-C contributed to the generation of the mouse models and the characterization of B-cells in those animal models. MBF generated v-abl pro-B-cell lines and carried out V(D)J recombination and genetic instability experiments. CL performed 53BP1 immunofluorescence experiments. FD engineered the Parp-2f/f mouse model. LM-L, JF, and CA contributed to mouse models generation and flow cytometry studies. JM-C and CM contributed to mice immunization. AC and PA contributed to planned and designed experiments. JY and LD planned and designed experiments and performed experiments. JY, AC, and LD wrote the manuscript. All authors discussed the results and commented on the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Ludovic Deriano or José Yélamos.

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