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首页> 外文期刊>Nucleic Acids Research >Double-strand break repair deficiency in NONO knockout murine embryonic fibroblasts and compensation by spontaneous upregulation of the PSPC1 paralog
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Double-strand break repair deficiency in NONO knockout murine embryonic fibroblasts and compensation by spontaneous upregulation of the PSPC1 paralog

机译：壬二克隆鼠胚胎成纤维细胞的双链破解缺乏和通过分发的PSPC1伞菌的自发上调补偿

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摘要

NONO, SFPQ and PSPC1 make up a family of proteins with diverse roles in transcription, RNA processing and DNA double-strand break (DSB) repair. To understand long-term effects of loss of NONO, we characterized murine embryonic fibroblasts (MEFs) from knockout mice. In the absence of genotoxic stress, wild-type and mutant MEFs showed similar growth rates and cell cycle distributions, and the mutants were only mildly radiosensitive. Further investigation showed that NONO deficiency led to upregulation of PSPC1, which replaced NONO in a stable complex with SFPQ. Knockdown of PSPC1 in a NONO-deficient background led to severe radiosensitivity and delayed resolution of DSB repair foci. The DNA-dependent protein kinase (DNA-PK) inhibitor, NU7741, sensitized wild-type and singly deficient MEFs, but had no additional effect on doubly deficient cells, suggesting that NONO/PSPC1 and DNA-PK function in the same pathway. We tested whether NONO and PSPC1 might also affect repair indirectly by influencing mRNA levels for other DSB repair genes. Of 12 genes tested, none were downregulated, and several were upregulated. Thus, NONO or related proteins are critical for DSB repair, NONO and PSPC1 are functional homologs with partially interchangeable functions and a compensatory response involving PSPC1 blunts the effect of NONO deficiency.
机译：Nono，SFPQ和PSPC1构成了一系列蛋白质，具有不同作用的转录，RNA处理和DNA双链突破（DSB）修复。为了了解偏离损失的长期影响，我们将来自敲除小鼠的小鼠胚胎成纤维细胞（MEF）表征。在没有遗传毒性应激的情况下，野生型和突变体MEF显示出类似的生长速率和细胞循环分布，并且突变体仅具有温和的放射敏感性。进一步的研究表明，非缺乏缺乏导致PSPC1的上调，其在具有SFPQ的稳定复合物中替换壬二。 PSPC1在非缺陷背景中的敲低导致了严重的放射敏感性和DSB修复灶的延迟分辨率。 DNA依赖性蛋白激酶（DNA-PK）抑制剂，Nu7741，敏化的野生型和单独缺乏的MEF，但对双缺乏细胞没有额外的影响，表明在同一途径中的非-PC1和DNA-PK功能。我们测试了Nono和PSPC1是否也可以通过影响其他DSB修复基因的mRNA水平间接影响修复。在测试的12个基因中，没有下调，几个是上调的。因此，非诺或相关蛋白对DSB修复至关重要，非族和PSPC1是具有部分可互换功能的功能性同源物，并且涉及PSPC1的补偿响应甚至缺乏缺乏的效果。

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