Cellular responses to DNA damage include activation of DNA-dependent protein kinase (DNA-PK) through, among others, the serine/threonine protein phosphatase 6 (PP6). We previously showed that recognition of DNA-PKcs is mediated by the SAPS1 PP6 regulatory subunit. Here, we report and characterize a SAPS1 null mouse and investigate the effects of deletion on DNA damage signaling and repair. Strikingly, neither SAPS1-null animals nor cells derived from them show gross defects, unless subjected to DNA damage by radiation or chemical agents. The overall survival of SAPS1-null animals following whole body irradiation is significantly shortened as compared to wild-type mice, and the clonogenic survival of null cells subjected to ionizing radiation is reduced. The dephosphorylation of DNA damage/repair markers, such as γH2AX, p53 and Kap1, is diminished in SAPS1-null cells as compared to wild-type controls. Our results demonstrate that loss of SAPS1 confers sensitivity to DNA damage and confirms previously reported cellular phenotypes of SAPS1 knock-down in human glioma cells. The results support a role for PP6 regulatory subunit SAPS1 in DNA damage responses, and offer a novel target for sensitization to enhance current tumor therapies, with a potential for limited deleterious side effects.

中文翻译：

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在小鼠中删除蛋白质磷酸酶6的SAPS1亚基会增加放射敏感性，并损害细胞DNA损伤反应。

细胞对DNA损伤的反应包括通过丝氨酸/苏氨酸蛋白磷酸酶6（PP6）等激活DNA依赖性蛋白激酶（DNA-PK）。我们以前表明，DNA-PKcs的识别是由SAPS1 PP6调节亚基介导的。在这里，我们报告和表征SAPS1空小鼠和调查删除对DNA损伤信号传导和修复的影响。引人注目的是，除非受到辐射或化学试剂的DNA破坏，否则没有SAPS1基因的动物或衍生自它们的细胞都不会显示出严重的缺陷。与野生型小鼠相比，全身照射后SAPS1无效动物的总体存活期显着缩短，受到电离辐射的无效细胞的克隆形成存活期降低。DNA损伤/修复标记（例如γH2AX，p53和Kap1）的去磷酸化，与野生型对照相比，SAPS1无细胞中的Aβ1减少。我们的结果表明，SAPS1的丧失赋予了对DNA损伤的敏感性，并证实了先前报道的人类神经胶质瘤细胞中SAPS1敲除的细胞表型。结果支持PP6调节亚基SAPS1在DNA损伤反应中的作用，并提供了新的致敏靶标，以增强当前的肿瘤疗法，并具有有限的有害副作用。