Mechanisms coordinating ELAV/Hu mRNA regulons

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The 5′ and 3′ untranslated regions (UTRs) of messenger RNAs (mRNAs) function as platforms that can determine the fate of each mRNA individually and in aggregate. Multiple mRNAs that encode proteins that are functionally related often interact with RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) that coordinate their expression in time and space as RNA regulons within the ribonucleoprotein (RNP) infrastructure we term the ribonome. Recent ribonomic methods have emerged that can determine which mRNAs are bound and regulated by RBPs and ncRNAs, some of which act in combination to determine global outcomes. ELAV/Hu proteins bind to AU-rich elements (ARE) in mRNAs and regulate their stability from splicing to translation, and the ubiquitous HuR protein has been implicated in cancerous cell growth. Recent work is focused on mechanistic models of how ELAV/Hu proteins increase mRNA stability and translation by repressing microRNAs (miRs) and the RNA induced silencing complex (RISC) via ARE-based ribonucleosomes that may affect global functions of mRNA regulons.

Section snippets

ELAV/Hu proteins bind A/G-UUU rich RNA sequences while stabilizing and/or activating translation of targeted mRNAs

The highly conserved ELAV/Hu family of RBPs consists of four family members, including three that are predominantly cytoplasmic and neuron-specific (HuB/Hel-N1, HuC and HuD) and one that is expressed primarily in the nucleus of all human cells (HuA/HuR) (reviewed in [11, 12, 13, 14]). Each Hu protein consists of three RNA recognition motifs (RRMs) and a flexible hinge/linker region between RRM2 and RRM3 [11]. Using several assays including UV crosslinking procedures, our lab discovered that HuB

ELAV/Hu proteins cooperatively form multimeric “ribonucleosomes”

An early observation regarding the functions of ELAV/Hu RBPs was that they bind to A/G-U rich sequences and form multimeric (or oligomeric) RNPs when binding to RNA targets [15, 31]. For example, a uniform array of progressively shifted HuB–RNA complexes was observed using gel mobility shifts suggesting that multiple protein molecules bind to a targeted mRNA in a concentration-dependent manner [15]. Similar findings were subsequently reported for HuD using an in vivo chemical crosslinking

The troika of coordinated gene expression

Gene expression is coordinated by three known mechanisms: (i) DNA operons/regulons, (ii) promoter-based transcription initiation, and (iii) RNA operons/regulons [4, 9••, 39, 40, 41]. In bacteria, DNA operons represent genes that function together and are physically grouped on the chromosome, but also by transcription factors that function at each promoter site. Eukaryotes also use promoter-based gene coordination, but they do not generally have traditional DNA operons. Genes that function

Transcriptomic and ribonomic analysis of gene expression

One of the inherent problems with simple transcriptomic methods such as RNA-seq is that they only detect the net accumulation of each type of mRNA. In fact, such “steady state” or accumulated levels depend not only on rates of RNA synthesis but also on rates of decay. Recent methods, such as 4-thiouridine pulsing [48], allow these two competing processes to be discriminated because newly synthesized mRNA can be separated from “old” partially decayed mRNA. These and other ribonomic methods have

Mechanistic models of ELAV/Hu effects on miRNPs and implications in oncogenesis

As noted above, early indications that over expression of ELAV proteins HuB and HuR stabilize ARE-containing mRNAs helped explain how synthesis of the encoded target proteins increases [16, 17, 21, 22, 23, 24, 25, 65]. There have been many attempts to address how HuR may affect mRNA functions through interactions with microRNAs. One of the first proposed mechanistic explanations for increased translation of a HuR mRNA target was discovered using the cationic amino acid transporter 1 (CAT1)

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

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