Regulatory RNAs derived from transfer RNA?
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 USA
2Program in Cell and Developmental Dynamics, University of Massachusetts Medical School, Worcester, Massachusetts 01605 USA
Four recent studies suggest that cleavages of transfer RNAs generate products with microRNA-like features, with some evidence of
function. If their regulatory functions were to be confirmed, these newly revealed RNAs would add to the expanding repertoire
of small noncoding RNAs and would also provide new perspectives on the coevolution of transfer RNA and messenger RNA.
Keywords: Argonautes; deep sequencing; microRNAs; transfer RNA
DEEP SEQUENCING REVEALS TRANSFER
RNA-DERIVED REGULATORY RNAS
The discovery of microRNAs was a milestone in the modern
era of biology (Lee et al. 1993; Wightman et al. 1993). The
many hundreds of microRNAs in an organism are processed
RNAs, or from genes that have evolved to produce only
microRNAs. Related pathways produce endogenous small
interfering RNAs and the germline-expressed piRNAs
(Ghildiyal and Zamore 2009). Now, four nearly contem-
poraneous papers have revealed another class of small non-
coding RNAs with microRNA features. They are derived
from a pioneer entry in the RNA discovery chain: transfer
RNA (Hoagland 2004).
There had been previous reports of transfer RNA-derived
fragments (Lee and Collins 2005; Calabrese et al. 2007;
Babiarz et al. 2008; Kawaji et al. 2008). But, the new work
reviewed here took this to a more refined analytical depth
function of transfer RNA-derived microRNA-like RNAs.
First in the current wave of studies was an investigation of
small RNAs in HIV-infected cells (Yeung et al. 2009). In
addition to detecting several small noncoding RNAs that
were known from previous work to be processed from the
viral RNA itself, this study revealed the presence in HIV-
infected cells of a small RNA corresponding to nucleotides
(PBS) in the genomic HIV, where it serves as the primer for
reverse transcription. Additional experiments demonstrated
that the cellular prevalence of this 20-nucleotide (nt) RNA
derived small RNA was bound to a canonical Argonaute
protein, Ago 2; that it could silence a luciferase reporter en-
this RNA to the HIV RNA PBS is a substrate for Dicer
cleavage in vitro.
Only 2 mo later, Lee et al. (2009) reported a deep-
sequencing analysis of total small RNAs from two human
prostatic carcinoma cell lines. They got >600,000 reads that
included 635 out of the 695 microRNAs in the Sanger
database. Among the remainder they found 17 RNAs, 18–
22 nt in length, that aligned with transfer RNA sequences.
Five were derived from the 59 ends of mature tRNAs, eight
were derived from the 39 ends of mature tRNAs, and four
were derived from the 39 trailer regions of pre-tRNAs. The
cloning coverage indicated that these tRNA-related small
RNAs are more abundant in these cells than the majority
of microRNAs, and are within an order of magnitude as
abundant as the most prevalent microRNAs. Spirited by
these findings, Lee et al. (2009) dove back into the pot of
all the other noncanonical microRNAs in their library (i.e.,
ones not in the Sanger database) and turned up another 621
that correspond to tRNA sequences (this large number
smaller number of tRNA species).
of their RNAs, tRF-1001, which corresponds to the 39 trailer
of pre-tRNASerTGA. They found that it displayed an elevated
and tissues and that, among the cell lines, its expression
was correlated with proliferation rate. They succeeded in
Reprint requests to: Thoru Pederson, Department of Biochemistry and
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Article published online ahead of print. Article and publication date are
RNA (2010), 16:1865–1869. Published by Cold Spring Harbor Laboratory Press. Copyright ? 2010 RNA Society.