Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C >G: p.171P >R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C >G mutation causes an ∼3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C >G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C >X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C >G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C >G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically.

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doi.org/10.1016/j.dnarep.2010.07.001, hdl.handle.net/1765/20819
D N A Repair
Erasmus MC: University Medical Center Rotterdam

Woodbine, L, Grigoriadou, S, Goodarzi, A.A, Riballo, E, Tape, C, Oliver, A.W, … Jeggo, P.A. (2010). An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity. D N A Repair, 9(9), 1003–1010. doi:10.1016/j.dnarep.2010.07.001