The following is a summary of “MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks,” published in the April 2024 issue of Allergy & Immunology by Mathias, et al.
Patients harboring deleterious variants in MYSM1 exhibit immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1, a histone deubiquitinase, plays a crucial role in gene expression regulation and localizes to DNA injury sites, yet its role in cellular responses to DNA breaks remains unclear. For a study, researchers sought to elucidate MYSM1’s activity in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) occurring during immunoglobulin receptor gene (Ig) recombination and induced by ionizing radiation.
MYSM1-deficient pre-B and non-B cells were employed to assess MYSM1’s involvement in DSB generation, repair, and DDR termination.
A novel splice variant in MYSM1, leading to nearly absent protein expression, was identified in a newborn with severe combined immune deficiency. Radiosensitivity testing in the patient’s peripheral blood lymphocytes revealed constitutive γH2AX expression in B cells without irradiation, implicating MYSM1 in DSB response during Ig recombination. However, suppression of MYSM1 in pre-B cells did not affect Ig DSB generation or repair. Instead, MYSM1 loss resulted in prolonged DNA damage foci and DDR signaling. Similar protracted DDRs were observed in U2OS cells with radiation-induced DSBs upon MYSM1 depletion.
While MYSM1 does not participate in DNA break generation and repair, it regulates DDR termination, indicating its crucial role in maintaining genomic stability and resolving DNA damage responses.
Reference: sciencedirect.com/science/article/pii/S0091674923024089