An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity

作者：Woodbine Lisa; Grigoriadou Sofia; Goodarzi Aaron A; Riballo Enriqueta; Tape Christopher; Oliver Antony W; van Zelm Menno C; Buckland Matthew S; Davies E Graham; Pearl Laurence H; Jeggo Penny A^*

来源：DNA Repair, 2010, 9(9): 1003-1010.

DOI：10.1016/j.dnarep.2010.07.001

• DNA double strand break repair
• Radiosensitivity
• Immunodeficiency
• V(D)J recombination

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 similar to 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.

• 出版日期2010-9-4