tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma
tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma
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DOI：
10.1073/pnas.1206761110
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发表时间：
2013-01-22
影响因子：
11.1
通讯作者：
Dalla-Favera, Riccardo
中科院分区：
文献类型：
--
作者：
Maute, Roy L.;Schneider, Christof;Dalla-Favera, Riccardo
来自几个模型系统的测序研究表明，各种各样和丰富的小RNA可能来自tRNA，但这些分子的功能仍然不确定。在这里，我们证明了这样一个tRNA衍生的片段，从人类成熟的B细胞中克隆出来，命名为CU1276，实际上具有microRNA的功能特征，包括依赖DICER1的生物发生，与ArgAerte蛋白质的物理结合，以及以序列特异性的方式抑制mRNA转录的能力。CU1276在正常生发中心B细胞中大量表达，但在生发中心来源的淋巴瘤中不表达，提示CU1276在本病的发病机制中起一定作用。此外，CU1276抑制内源性RPA1，这是参与DNA动力学许多方面的一个必要基因，因此，这种tRNA衍生的microRNA在淋巴瘤细胞系中的表达抑制了细胞的增殖，并调节了对DNA损伤的分子反应。这些结果证实了具有功能活性的microRNAs可以从tRNA中衍生出来，从而定义了一类具有潜在重要生物学作用的遗传实体。
Sequencing studies from several model systems have suggested that diverse and abundant small RNAs may be derived from tRNA, but the function of these molecules remains undefined. Here, we demonstrate that one such tRNA-derived fragment, cloned from human mature B cells and designated CU1276, in fact possesses the functional characteristics of a microRNA, including a DICER1-dependent biogenesis, physical association with Argonaute proteins, and the ability to repress mRNA transcripts in a sequence-specific manner. Expression of CU1276 is abundant in normal germinal center B cells but absent in germinal center-derived lymphomas, suggesting a role in the pathogenesis of this disease. Furthermore, CU1276 represses endogenous RPA1, an essential gene involved in many aspects of DNA dynamics, and consequently, expression of this tRNA-derived microRNA in a lymphoma cell line suppresses proliferation and modulates the molecular response to DNA damage. These results establish that functionally active microRNAs can be derived from tRNA, thus defining a class of genetic entities with potentially important biological roles.