Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1404-9. doi: 10.1073/pnas.1206761110. Epub 2013 Jan 7.
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.
来自多个模式系统的测序研究表明，多样化且丰富的小 RNA 可能来自 tRNA，但这些分子的功能仍未定义。在这里，我们证明了从人成熟 B 细胞克隆的此类 tRNA 衍生片段，命名为 CU1276，实际上具有 microRNA 的功能特征，包括 DICER1 依赖性生物发生、与 Argonaute 蛋白的物理关联以及以序列特异性方式抑制 mRNA 转录的能力。CU1276 在正常生发中心 B 细胞中表达丰富，但在生发中心衍生的淋巴瘤中缺失，提示其在该疾病的发病机制中发挥作用。此外，CU1276 抑制内源性 RPA1，这是一个参与 DNA 动力学许多方面的必需基因，因此，淋巴瘤细胞系中这种 tRNA 衍生 microRNA 的表达会抑制增殖并调节对 DNA 损伤的分子反应。这些结果表明，具有功能活性的 microRNA 可以来自 tRNA，从而定义了一类具有潜在重要生物学作用的遗传实体。
