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Full-length hdmX transcripts decrease following genotoxic stress

机译：遗传毒性胁迫后全长hdmX转录产物减少

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Previous studies have suggested that the mdmX gene is constitutively transcribed, and that MdmX protein activity is instead controlled by cellular localization and DNA damage induced Mdm2-mediated ubiquitination leading to proteasomal degradation. In these studies, we report that the human mdmX (hdmX) mRNA is reproducibly decreased in various human cell lines following treatment with various DNA-damaging agents. Repression of hdmX transcripts is observed in DNA-damaged HCT116 colon cancer cells and in isogenic p53?/? cells, suggesting that this effect is p53-independent. Reduction in the amount of hdmX transcript occurs in both human tumor cell lines and primary human diploid fibroblasts, and results in a significant reduction of HdmX protein. Examination of hdmX promoter activity suggests that damage-induced repression of hdmX mRNA is not significantly impacted by transcription initiation. In contrast, changes in hdmX mRNA splicing appear to partly explain the reduction in full-length hdmX mRNA levels in tumor cell lines with the destabilization of full-length hdmX transcripts, potentially through microRNA miR-34a regulation, also impacting transcript levels. Taken together, this study uncovers previously unrecognized cellular mechanisms by which hdmX mRNA levels are kept low following genotoxic stress.
机译：先前的研究表明，mdmX基因是组成型转录的，而MdmX蛋白的活性由细胞定位控制，DNA损伤诱导的Mdm2介导的泛素化导致蛋白酶体降解。在这些研究中，我们报告了人类mdmX（hdmX）mRNA在用各种DNA破坏剂处理后在各种人类细胞系中可再现地降低。在DNA损伤的HCT116结肠癌细胞和同基因的p53β/β中观察到hdmX转录物的抑制。细胞，表明此效应是p53独立的。在人类肿瘤细胞系和原代人类二倍体成纤维细胞中，hdmX转录物数量的减少，并导致HdmX蛋白的显着减少。对hdmX启动子活性的检查表明，转录诱导不会显着影响损伤诱导的hdmX mRNA的抑制。相反，hdmX mRNA剪接的变化似乎可以部分解释肿瘤细胞系中全长hdmX mRNA水平的降低，原因可能是全长hdmX转录本不稳定，可能通过microRNA miR-34a调控，也影响转录本水平。两者合计，这项研究发现了以前无法识别的细胞机制，通过该机制，在遗传毒性胁迫后，hdmX mRNA的水平保持较低水平。

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