Small Non-coding Transfer RNA-Derived RNA Fragments (tRFs): Their Biogenesis, Function and Implication in Human Diseases

Fu, Yu; Lee, Inhan; Lee, Yong Sun; Bao, Xiaoyong

Other reasons supporting that tRFs are biologically meaningful include their endonuclease-specific cleavage [3, 4, 34, 42] . The production of the tRF-5 series has been reported to be Dicer or angiogenin (ANG)-dependent in mammals [33, 34] . In one case, the tRF-5 series were identified to be produced after the hybridization of the 3ËŠ-end of the human cellular tRNA lys with the HIV-1 primer binding site, raising the possibility that, at least in certain cases, tRFs may be produced when a tRNA base-pairs with another RNA molecule [38] . It has been reported that the tRF-3 series are generated by Dicer [32, 38] . In Tetrahymena, although the nuclease identity was not proven, the tRF-3 series have 5ËŠmonophosphates that are usually left after Dicer cleavage and are in physical association with Argonaute/Piwi proteins, suggesting Dicer-mediated cleavage [39] . The tRNA 3ËŠ-trailer sequences are thought to be rapidly degraded in the nuclear compartment soon after being cleaved from pre-tRNAs. Therefore, it is quite surprising that the tRF-1 series are localized mainly in the cytoplasm [3, 41] . There are two explanations on how the tRF-1 series bypass nuclear cleavage: (1) the tRF-1 series are exported from the nucleus by an unknown mechanism upon processing, or (2) pre-tRNAs escape nuclear quality control and are processed by cytoplasmic RNase Z. Biological evidence indeed supports the second possibility. At least in one case of a tRF-1 molecule derived from tRNA Ser (termed tRF-1001 [3] and Cand45 [32] ), the corresponding pre-tRNA is localized in the cytoplasm [3, 32] . Also there are several reports supporting the cytoplasmic localization of tRNA endonucleases responsible for the tRF-1 series [3, 43] .