title: An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity.
abstract: 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 approximately 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.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Woodbine
authors.forename: Sofia
authors.initials: S
authors.lastname: Grigoriadou
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Goodarzi
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Riballo
authors.forename: Christopher
authors.initials: C
authors.lastname: Tape
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Buckland
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D000818:Animals; D019306:Artemisia / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D011110:Polymorphism, Genetic; D011836:Radiation Tolerance
chemical_list: D017931:DNA Primers