Woodbine, Lisa, Grigoriadoub, Sofia, Goodarzi, Aaron A, Riballo, Enriqueta, Tape, Christopher, Oliver, Antony W, van Zelm, Menno C, Buckland, Matthew S, Davies, E Graham, Pearl, Laurence H and Jeggo, Penny A (2010) An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity. DNA Repair, 9 (9). pp. 1003-1010. ISSN 1568-7864

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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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User:	Lisa Woodbine
Date Deposited:	06 Feb 2012 20:14
Last Modified:	02 Apr 2012 08:23
URI:	http://sro.sussex.ac.uk/id/eprint/24886

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