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 play 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.

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

“…A possible explanation for this bone marrow hypocellularity is that the V(D)J recombination process is defective in these cells. However, a detailed analysis showed that neither single nor double PARP-1/PARP-2 deficiency affected Ig V(D)J gene recombination [36]. As in the T cell compartment, B cell lymphopenia in dually PARP-1-and PARP-2-deficient mice is associated with an accumulation of unrepaired DNA damage in proliferating B cells leading to cell death, suggesting a potential model whereby coordinated signals from PARP-1 and PARP-2 are required to maintain genomic integrity during lymphoid proliferation.…”

“…In the first step, the hematopoietic stem cells differentiate into pro-B cells that transiently express the Rag genes, which mediate immunoglobulin (Ig [33][34][35]. Recent data obtained by our group show that mice with dual, but not individual, PARP-1 and PARP-2 deficiency exhibit a reduced number of B cells in the bone marrow [36] ( Figure 2). A possible explanation for this bone marrow hypocellularity is that the V(D)J recombination process is defective in these cells.…”

“…Cancers 2020, 12, x 5 of 18 B cells in the bone marrow [36] (Figure 2). A possible explanation for this bone marrow hypocellularity is that the V(D)J recombination process is defective in these cells.…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…Additional studies used PARP1-deficiet mice further demonstrated mechanisms for PARP1-regulated suppression of Tregs via transforming growth factor β (TGF β) receptors . Recent reports demonstrate the interactive role of PARP1 and PARP2 in maintaining the number and function of T cells and promoting the development and function of B cells (Navarro et al 2017;Galindo-Campos et al 2019). Defective thymocyte maturation is observed in PARP1/PARP2-deficient mice, and accordingly T-cell numbers in peripheral blood are reduced (Galindo-Campos et al 2019).…”

“…Recent reports demonstrate the interactive role of PARP1 and PARP2 in maintaining the number and function of T cells and promoting the development and function of B cells (Navarro et al 2017;Galindo-Campos et al 2019). Defective thymocyte maturation is observed in PARP1/PARP2-deficient mice, and accordingly T-cell numbers in peripheral blood are reduced (Galindo-Campos et al 2019). In PARP1/PARP2-deficient mice, the development of bone marrow B cells is impaired, leading to the reduction of transitional and follicular B cells (Navarro et al 2017).…”