Alu elements are the most abundant repetitive elements in the human genome; they emerged 65 million years ago from a 5′ to 3′ fusion of the 7SL RNA gene and amplified throughout the human genome by retrotransposition to reach the present number of more than one million copies. Over the last years, several lines of evidence demonstrated that these elements modulate gene expression at the post-transcriptional level in at least three independent manners. They have been shown to be involved in alternative splicing, RNA editing and translation regulation. These findings highlight how the genome adapted to these repetitive elements by assigning them important functions in regulation of gene expression. Alu elements should therefore be considered as a large reservoir of potential regulatory functions that have been actively participating in primate evolution.

Abstract. Alu elements are the most abundant repetitive elements in the human genome; they are amplified by retrotransposition to reach the present number of more than one million copies. Alu elements can be transcribed in two different ways, by two independent polymerases. Free Alu RNAs are transcribed by Pol III from their own promoter, while embedded Alu RNAs are transcribed by Pol II as part of protein-and non-protein-coding RNAs. Recent studies have demonstrated that both free and embedded Alu RNAs play a major role in posttranscriptional regulation of gene expression, for example by affecting protein translation, alternative splicing and mRNA stability. These discoveries illustrate how a part of the junk DNA content of the human genome has been recruited to important functions in regulation of gene expression.

Alu elements are the most abundant repetitive elements in the human genome; they emerged from the signal recognition particle RNA gene and are composed of two related but distinct monomers (left and right arms). Alu RNAs transcribed from these elements are present at low levels at normal cell growth but various stress conditions increase their abundance. Alu RNAs are known to bind the cognate proteins SRP9/14. We purified synthetic Alu RNP, composed of Alu RNA in complex with SRP9/14, and investigated the effects of Alu RNPs and naked Alu RNA on protein translation. We found that the dimeric Alu RNP and the monomeric left and right Alu RNPs have a general dose-dependent inhibitory effect on protein translation. In the absence of SRP9/14, Alu RNA has a stimulatory effect on all reporter mRNAs. The unstable structure of sRight RNA suggests that the differential activities of Alu RNP and Alu RNA may be explained by conformational changes in the RNA. We demonstrate that Alu RNPs and Alu RNAs do not stably associate with ribosomes during translation and, based on the analysis of polysome profiles and synchronized translation, we show that Alu RNP and Alu RNA regulate translation at the level of initiation.

Activation-induced cytidine deaminase (AID) is a B lymphocytespecific DNA deaminase that acts on the Ig loci to trigger antibody gene diversification. Most AID, however, is retained in the cytoplasm and its nuclear abundance is carefully regulated because off-target action of AID leads to cancer. The nature of the cytosolic AID complex and the mechanisms regulating its release from the cytoplasm and import into the nucleus remain unknown. Here, we show that cytosolic AID in DT40 B cells is part of an 11S complex and, using an endogenously tagged AID protein to avoid overexpression artifacts, that it is bound in good stoichiometry to the translation elongation factor 1 alpha (eEF1A). The AID/eEF1A interaction is recapitulated in transfected cells and depends on the C-terminal domain of eEF1A (which is not responsible for GTP or tRNA binding). The eEF1A interaction is destroyed by mutations in AID that affect its cytosolic retention. These results suggest that eEF1A is a cytosolic retention factor for AID and extend on the multiple moonlighting functions of eEF1A. Functional Ig genes are produced in developing B-lymphocyte precursors by a process of V(D)J gene rearrangement catalyzed by the RAG1/2 recombinase. These rearranged IgV genes are then further diversified by either gene conversion in chicken (using proximal IgV pseudogenes as donors) or by somatic hypermutation in man and mouse (underpinning antibody affinity maturation). The isotype of the antibody can also be changed from IgM to IgG, IgA, or IgE through class-switch recombination.Ig gene conversion, somatic hypermutation, and class-switch recombination are all initiated by the B lymphocyte-specific enzyme AID, which deaminates cytosine residues within the IgV or switch regions, yielding localized U:G mismatches that are recognized by uracil-DNA glycosylase or MSH2/MSH6, thereby triggering the subsequent gene diversification processes (1).As an active DNA mutator, AID is a dangerous protein: its abundance appears to be carefully regulated. Ig gene diversification is reduced in cells hemizygous for AID: overexpression or ectopic expression of AID increases the frequency of chromosomal translocations and malignancies. The regulation of AID gene expression occurs both transcriptionally and posttranscriptionally (reviewed in ref.2).It is also likely that much regulation of AID occurs posttranslationally. Thus, AID is phosphorylated on several serine/threonine residues, some of which are critical for its function (3-8). Furthermore, although active in the nucleus, the majority of AID is detected in the cytoplasm where it cycles into and out of the nucleus (9-11). Whereas AID's nuclear export is mediated by a Crm1-dependent export sequence (9-11), the mechanism of its nuclear import is still unclear, although the work of Patenaude et al. (12) reveals that dissociation from an unidentified cytosolic retention factor may allow nuclear import with such import depending upon a noncontiguous cluster of basic amino acids in AID.We have been interested in advancin...