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: Lisa Woodbine, Sofia Grigoriadou, Aaron A Goodarzi, Enriqueta Riballo, Christopher Tape, Antony W Oliver, Menno C van Zelm, Matthew S Buckland, E Graham Davies, Laurence H Pearl, Penny A Jeggo
• Journal: DNA repair (DNA Repair (Amst)) Vol. 9 Issue 9 Pg. 1003-10 (Sep 04 2010) ISSN: 1568-7856 [Electronic] Netherlands
• PMID: 20674517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier B.V. All rights reserved.

Chemical References

• DNA Primers

Topics

• Animals
• Artemisia (genetics)
• Base Sequence
• DNA Primers
• Fluorescent Antibody Technique
• Polymorphism, Genetic
• Radiation Tolerance