A hypomorphic Artemis human disease allele causes aberrant chromosomal rearrangements and tumorigenesis

Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Human Molecular Genetics (Impact Factor: 6.39). 02/2011; 20(4):806-19. DOI: 10.1093/hmg/ddq524
Source: PubMed


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.

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