Double-strand break repair through homologous recombination in autosomal-recessive BCL10 deficiency

T-cell and B-cell counts revealed a profound deficit in memory T and B cells, a normal response in myeloid cells, and a strong effect on NF-κB–mediated fibroblast functions.3 Recent studies have highlighted the role of the CBM complex in DNA repair.4,5 Studies conducted with human cell lines have found that BCL10 can translocate to the nucleus and have shown that BCL10 functions as part of the DNA damage response. BCL10 facilitates the rapid recruitment of replication protein A (RPA), breast cancer gene 1 (BRCA1), and RAD51 to DNA damage sites, specifically mediating DNA double-strand break (DSB) repair via homologous recombination (HR).4,5 To analyze the role of BCL10 in both DNA repair pathways, we treated BCL10−/− cells immortalized by Simian Virus 40 (SV40) fibroblasts with hydroxyurea (HU) and hydrogen peroxide (H2O2) or γ-irradiated (3 Gy of ionizing radiation) to induce DSBs. The HR pathway plays a crucial role in preventing the development of cancer cells and could be used as a therapeutic target. Because of its role in maintaining genome integrity, the HR pathway is often considered the last resort for preventing tumorigenesis. Despite the patient's clinical outcome due to the mutation's severity, this study shows that future patients with new loss-of-function BCL10 mutations will have greater susceptibility to developing cancer because the HR repair pathway would be affected. [...]BCL10 overproduction has been implicated in MALT lymphoma, and several therapeutic studies have therefore attempted to inhibit CBM complex expression.9 Our observations of human BCL10−/− fibroblasts are highly pertinent and should be taken into account when considering treatment options for MALT lymphoma, given that BCL10 inhibition can affect the HR repair pathway and increase a patient's predisposition to malignancies.