期刊
CELL DEATH AND DIFFERENTIATION
卷 26, 期 12, 页码 2667-2681出版社
SPRINGERNATURE
DOI: 10.1038/s41418-019-0326-5
关键词
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资金
- Spanish Ministerio de Economia, Industria y Competitividad [SAF2014-52483-R, SAF2017-83565-R]
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC)
- Institut National du Cancer [PLBIO16-181]
- European Research Council under the ERC [310917]
- Institut Pasteur
- Strasbourg University, CNRS [LABEX ANR-10-LABX-0034_Medalis]
- European Research Council (European Advanced Grant) [ERC-2011ADG-20110310]
- CONACyT
- European Research Council (ERC) [310917] Funding Source: European Research Council (ERC)
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 beta-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, bonemarrow 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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