Woo Y, Wright S M, Maas S A, Alley T L, Caddle L B, Kamdar S, Affourtit J, Foreman O, Akeson E C, Shaffer D, Bronson R T, Morse H C, Roopenian D, Mills K D
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Oncogene. 2007 Sep 6;26(41):6010-20. doi: 10.1038/sj.onc.1210430. Epub 2007 Mar 26.
Nonhomologous end joining (NHEJ) is a critical DNA repair pathway, with proposed tumor suppression functions in many tissues. Mutations in the NHEJ factor ARTEMIS cause radiation-sensitive severe combined immunodeficiency in humans and may increase susceptibility to lymphoma in some settings. We now report that deficiency for Artemis (encoded by Dclre1c/Art in mouse) accelerates tumorigenesis in several tissues in a Trp53 heterozygous setting, revealing tumor suppression roles for NHEJ in lymphoid and non-lymphoid cells. We also show that B-lineage lymphomas in these mice undergo loss of Trp53 heterozygosity by allele replacement, but arise by mechanisms distinct from those in Art Trp53 double null mice. These findings demonstrate a general tumor suppression function for NHEJ, and reveal that interplay between NHEJ and Trp53 loss of heterozygosity influences the sequence of multi-hit oncogenesis. We present a model where p53 status at the time of tumor initiation is a key determinant of subsequent oncogenic mechanisms. Because Art deficient mice represent a model for radiation-sensitive severe combined immunodeficiency, our findings suggest that these patients may be at risk for both lymphoid and non-lymphoid cancers.
非同源末端连接（NHEJ）是一种关键的DNA修复途径，在许多组织中具有潜在的肿瘤抑制功能。NHEJ因子ARTEMIS的突变会导致人类对辐射敏感的重症联合免疫缺陷，并且在某些情况下可能增加患淋巴瘤的易感性。我们现在报告，Artemis（由小鼠中的Dclre1c/Art编码）缺陷在Trp53杂合背景下会加速多个组织中的肿瘤发生，揭示了NHEJ在淋巴细胞和非淋巴细胞中的肿瘤抑制作用。我们还表明，这些小鼠中的B细胞淋巴瘤通过等位基因替代导致Trp53杂合性缺失，但产生机制与Art Trp53双敲除小鼠不同。这些发现证明了NHEJ具有普遍的肿瘤抑制功能，并揭示了NHEJ与Trp53杂合性缺失之间的相互作用会影响多步骤肿瘤发生的顺序。我们提出了一个模型，其中肿瘤起始时的p53状态是后续致癌机制的关键决定因素。由于Art缺陷小鼠代表了对辐射敏感的重症联合免疫缺陷模型，我们的发现表明这些患者可能有患淋巴细胞和非淋巴细胞癌症的风险。
