title: A hypomorphic Artemis human disease allele causes aberrant chromosomal rearrangements and tumorigenesis.
abstract: The Artemis gene encodes a DNA nuclease that plays important roles in non-homologous end-joining (NHEJ), a major double-strand break (DSB) repair pathway in mammalian cells. NHEJ factors repair general DSBs as well as programmed breaks generated during the lymphoid-specific DNA rearrangement, V(D)J recombination, which is required for lymphocyte development. Mutations that inactivate Artemis cause a human severe combined immunodeficiency syndrome associated with cellular radiosensitivity. In contrast, hypomorphic Artemis mutations result in combined immunodeficiency syndromes of varying severity, but, in addition, are hypothesized to predispose to lymphoid malignancy. To elucidate the distinct molecular defects caused by hypomorphic compared with inactivating Artemis mutations, we examined tumor predisposition in a mouse model harboring a targeted partial loss-of-function disease allele. We find that, in contrast to Artemis nullizygosity, the hypomorphic mutation leads to increased aberrant intra- and interchromosomal V(D)J joining events. We also observe that dysfunctional Artemis activity combined with p53 inactivation predominantly predisposes to thymic lymphomas harboring clonal translocations distinct from those observed in Artemis nullizygosity. Thus, the Artemis hypomorphic allele results in unique molecular defects, tumor spectrum and oncogenic chromosomal rearrangements. Our findings have significant implications for disease outcomes and treatment of patients with different Artemis mutations.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Jacobs
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Tehmina
authors.initials: T
authors.lastname: Masud
authors.forename: William
authors.initials: W
authors.lastname: Lu
authors.forename: Gerwin
authors.initials: G
authors.lastname: Westfield
authors.forename: William
authors.initials: W
authors.lastname: Giblin
authors.forename: JoAnn M
authors.initials: JM
authors.lastname: Sekiguchi
mesh_terms: D000483:Alleles; D000818:Animals; D002869:Chromosome Aberrations; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004720:Endonucleases; D015321:Gene Rearrangement; D006801:Humans; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000378:metabolism*; D032681:Spectral Karyotyping; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C426344:DCLRE1C protein, human; D004720:Endonucleases; C473337:Dclre1c protein, mouse