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A novel radiosensitive SCID patient with a pronounced G2/M sensitivity
Ist Teil von
DNA repair, 2010-04, Vol.9 (4), p.365-373
Ort / Verlag
Amsterdam: Elsevier
Erscheinungsjahr
2010
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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 TaB+NK+ phenotype but without causative mutations in CD3I, E>, I or IL7Ra, 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 G1 M3 cells were indistinguishable from those obtained with normal cells. However, we found increased chromosomal radiosensitivity at the G2 phase 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.