Background: Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1 is a histone deubiquitinase with established activity in regulating gene expression. MYSM1 also localizes to sites of DNA injury but its function in cellular responses to DNA breaks has not been elucidated. Objectives: This study sought to determine the activity of MYSM1 in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) generated during immunoglobulin receptor gene (Ig) recombination and by ionizing radiation. Methods: MYSM1-deficient pre– and non–B cells were used to determine the role of MYSM1 in DSB generation, DSB repair, and termination of DDRs. Results: Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression. Radiosensitivity testing in patient's peripheral blood lymphocytes showed constitutive γH2AX, a marker of DNA damage, in B cells in the absence of irradiation, suggesting a role for MYSM1 in response to DSBs generated during Ig recombination. Suppression of MYSM1 in pre–B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling. Loss of MYSM1 also led to protracted DDRs in U2OS cells with irradiation induced DSBs. Conclusions: MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair.

Original languageEnglish
Pages (from-to)1113-1124.e7
JournalJournal of Allergy and Clinical Immunology
Issue number4
StatePublished - Apr 2024


  • B cells
  • DNA breaks
  • DNA damage response
  • DNA damage signaling
  • MYSM1
  • RAG
  • inborn error of immunity


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