Liu Yang, Zhao Xiaotong, Wang Bing, Liu Zhijia, Zhang Manman, Wang Jinhan, Xu Chang, Wang Yan, Du Liqing, Wang Feng, Wang Qin, Liu Qiang
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China.
Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Front Cell Dev Biol. 2021 Apr 16;9:649328. doi: 10.3389/fcell.2021.649328. eCollection 2021.
CTC1 is a component of the mammalian CST (CTC1-STN1-TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3'-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression CTC1 downregulating induced telomere dysfunction.
CTC1是哺乳动物CST（CTC1-STN1-TEN1）复合物的一个组成部分，该复合物在解决复制问题以促进端粒DNA和基因组DNA复制方面发挥着重要作用。我们之前报道过，CTC1的缺失会导致复制叉重启缺陷。此外，CTC1中的突变会引发包括科茨综合征（CP）或先天性角化不良（DC）在内的易患癌症的疾病。为了更好地理解CTC1调控轴，我们通过生物信息学工具预测了靶向CTC1的微小RNA（miRNA），并通过双荧光素酶报告基因检测进一步证实了所选的候选物。在这里，我们目前的结果显示，miR-376a通过识别CTC1的3'-UTR在转录水平上显著降低了CTC1的表达。此外，miR-376a的过表达诱导了端粒复制缺陷并导致直接的复制性端粒损伤，补充回CTC1可以挽救这种损伤。在miR-376a处理后也观察到了端粒缩短。此外，对于临床患者样本，miR-376a的高表达与CTC1的失调以及直肠腺癌患者的不良预后相关。总之，我们的结果揭示了miR-376a在刺激直肠腺癌进展中通过下调CTC1诱导端粒功能障碍的新作用。
