Snm1-deficient mice exhibit accelerated tumorigenesis and susceptibility to infection
Snm1-deficient mice exhibit accelerated tumorigenesis and susceptibility to infection
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DOI：
10.1128/mcb.25.22.10071-10078.2005
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发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Legerski, RJ
中科院分区：
文献类型：
--
作者：
Ahkter, S;Richie, CT;Legerski, RJ
真核SNM1基因家族参与了许多细胞通路，包括DNA链间交联的修复，参与VDJ重组，DNA双链断裂的修复，以及参与细胞周期检查点通路。特别是，哺乳动物SNM1已被证明在有丝分裂检查点中是必需的，该检查点在响应纺锤体毒物的染色体凝聚之前导致细胞在前期停滞。在这里，我们报道了小鼠Snm1基因敲除的表型。Snm1（-/-）小鼠是可存活和可生育的，但表现出复杂的表型。纯合子和杂合子小鼠的存活率都比野生型小鼠低。在纯合子突变的雄性中，这种存活率的降低主要是由于包皮和下颌腺的细菌感染，在较小程度上是由于肿瘤的发生，而在纯合子和杂合子突变的雌性中，几乎完全是由于肿瘤的发生。纯合子突变体男性细菌感染的高发生率提示免疫功能障碍；然而，T细胞和b细胞发育和免疫球蛋白类转换的检查并没有揭示这些途径的缺陷。Snm1突变小鼠与Trp53零突变体杂交导致死亡率增加，肿瘤类型限制为淋巴瘤，特别是胸腺肿瘤。综上所述，这些发现表明Snm1在小鼠中是一种肿瘤抑制因子，此外还在免疫中发挥作用。
The eukaryotic SNM1 gene family has been implicated in a number of cellular pathways, including repair of DNA interstrand cross-links, involvement in VDJ recombination, repair of DNA double-strand breaks, and participation in cell cycle checkpoint pathways. In particular, mammalian SNM1 has been shown to be required in a mitotic checkpoint that causes arrest of cells in prophase prior to chromosome condensation in response to spindle poisons. Here, we report on the phenotype of a knockout of Snm1 in the mouse. Snm1(-/-) mice are viable and fertile but exhibit a complex phenotype. Both homozygous and heterozygous mice show a decline in survival compared to wild-type littermates. In homozygous mutant males, this reduction in survival is principally due to bacterial infections in the preputial and mandibular glands and to a lesser extent to tumorigenesis, while in homozygous and heterozygous females, it is due almost solely to tumorigenesis. The high incidence of bacterial infections in the homozygous mutant males suggests an immune dysfunction; however, examinations of T- and B-cell development and immunoglobulin class switching did not reveal a defect in these pathways. Crossing of Snm1 mutant mice with a Trp53 null mutant resulted in an increase in mortality and a restriction of the tumor type to lymphomas, particularly those of the thymus. Taken together, these findings demonstrate that Snm1 is a tumor suppressor in mice that in addition has a role in immunity.