V(D)J rearrangement in lymphoid cells involves repair of double-strand breaks (DSBs) through non-homologous end joining (NHEJ). Defects in this process lead to increased radiosensitivity and severe combined immunodeficiency (RS-SCID). Here, a SCID patient, M3, is described with a T-B+NK+phenotype but without causative mutations in CD3δ, ε, ζ or IL7Rα, genes specifically involved in T cell development. Clonogenic survival of M3 fibroblasts showed an increased sensitivity to the DSB-inducing agents ionizing radiation and bleomycin, as well as the crosslinking compound, mitomycin C. We did not observe inactivating mutations in known NHEJ genes and results of various DSB-repair assays in G1M3 cells were indistinguishable from those obtained with normal cells. However, we found increased chromosomal radiosensitivity at the G2phase of the cell cycle. Checkpoint analysis indicated functional G1/S and intra-S checkpoints after irradiation but impaired activation of the "early" G2/M checkpoint. Together these results indicate a novel class of RS-SCID patients characterized by the specific absence of T lymphocytes and associated with defects in G2-specific DSB repair. The pronounced G2/M radiosensitivity of the RS-SCID patient described here, suggests a defect in a putative novel and uncharacterized factor involved in cellular DNA damage responses and T cell development.

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Keywords Immunodeficiency, Repair defect, X-ray sensitivity
Persistent URL dx.doi.org/10.1016/j.dnarep.2009.12.004, hdl.handle.net/1765/28582
Citation
Wiegant, W.W, Meyers, M, Verkaik, N.S, van der Burg, M, Darroudi, F, Romeijn, R, … Zdzienicka, M.Z. (2010). A novel radiosensitive SCID patient with a pronounced G2/M sensitivity. D N A Repair, 9(4), 365–373. doi:10.1016/j.dnarep.2009.12.004