Deletion of the SAPS1 subunit of protein phosphatase 6 in mice increases radiosensitivity and impairs the cellular DNA damage response
Deletion of the SAPS1 subunit of protein phosphatase 6 in mice increases radiosensitivity and impairs the cellular DNA damage response
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DOI：
10.1016/j.dnarep.2019.102737
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发表时间：
2020-01-01
期刊：
影响因子：
3.8
通讯作者：
Larner, James M.
中科院分区：
文献类型：
--
作者：
Dziegielewski, Jaroslaw;Bonkowska, Magdalena A.;Larner, James M.
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)激活DNA依赖的蛋白激酶(DNA-PK)。我们以前的研究表明，DNA-PKcs的识别是由SAPS1 PP6调节亚基介导的。在这里，我们报告和表征了SAPS1缺失的小鼠，并研究了缺失对DNA损伤信号和修复的影响。引人注目的是，SAPS1缺失的动物及其衍生的细胞都没有明显的缺陷，除非受到辐射或化学物质对DNA的破坏。与野生型小鼠相比，SAPS1缺失型动物全身照射后的总体存活时间显著缩短，而受到电离辐射的缺失型动物的克隆存活率降低。与野生型对照相比，SAPS1缺失的细胞中DNA损伤/修复标记物的去磷酸化程度降低，如伽马H_2AX、P53和KAP1。我们的结果表明，SAPS1的缺失使人胶质瘤细胞对DNA损伤具有敏感性，并证实了先前报道的SAPS1基因敲除的细胞表型。这些结果支持PP6调节亚基SAPS1在DNA损伤反应中的作用，并提供了一个新的增敏靶点，以加强当前的肿瘤治疗，具有潜在的有限有害副作用。
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 gamma H2AX, 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.