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

Poly (ADP-ribose) polymerase and regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD⁺. Hence, mice lacking or Pduanyu37-2 show DNA perturbations ranging from altered DNA integrity to impaired DNA repair. These effects stem from the central role that Pduanyu37-1 and Pduanyu37-2 have on the cellular response to DNA damage. Failure to mount a proper response culminates in cell death. Accordingly, 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 Pduanyu37-1 and Pduanyu37-2 deficiency develop early embryonic lethality, we crossed mice with mice carrying a B-cell-conditional Pduanyu37-2 gene deletion. We found that the resulting dually Pduanyu37-1 and 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 Pduanyu37-1 or Pduanyu37-2 deficiency. In dually Pduanyu37-1 and Pduanyu37-2-deficient mice, B-cell lymphopenia was associated with increased DNA damage and accentuated death in actively proliferating B-cells. Moreover, dual Pduanyu37-1 and Pduanyu37-2 deficiency impaired antibody responses to T-independent carbohydrate but not to T-dependent protein antigens. Notwithstanding the pivotal role of Pduanyu37-1 and Pduanyu37-2 in DNA repair, combined Pduanyu37-1 and Pduanyu37-2 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 Pduanyu37 inhibitors on humoral immunity, which will facilitate the development of safer regimens against cancer.

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