The International Journal of Biochemistry & Cell Biology
Molecules in focusRBM4: A multifunctional RNA-binding protein
Introduction
In eukaryotic cells, mRNAs undergo numerous steps of regulation between transcription and translation. These include splicing, transport, stability and localization. The coordination of these processes is controlled by ribonucleoprotein complexes (RNPs) containing RNA-binding proteins (RBPs), small nuclear ribonucleoproteins (snRNPs) and small non-coding RNAs. RBPs have emerged as some of the most versatile molecules in the cell, revealing roles in nearly every cellular process. Reflecting their multiple activities, they can be detected in various subcellular organelles, such as speckles, nucleoli, Cajal bodies, P-bodies and stress granules.
Mammalian homologues of Lark, first identified in Drosophila, have turned out to resemble other RBPs in having multiple functions affecting diverse cellular processes, and are present in several different subcellular compartments.
Section snippets
Structure
Lark is termed RBM4 in mammals, and is highly conserved throughout evolution (Markus and Morris, 2006). The human RBM4 gene has 95% homology with the mouse gene, and 53% with the Xenopus homologue. Two isoforms of mammalian RBM4 have been reported—RBM4a and RBM4b. These are very similar in structure and sequence. In humans, both are located on chromosome 11q13, and in mouse are on chromosome 19A. Their sequence suggests they arose through gene duplication. Interestingly, the entire RBM4a gene
Expression and activation
RBM4 is expressed ubiquitously, with particularly strong levels in testis, ovaries, heart and pancreas, but conflicting results have been obtained for skeletal muscle. In murine skeletal muscle, RBM4 mRNA was absent. In human skeletal muscle, however, RBM4 is expressed strongly (Kojima et al., 2007, Lin and Tarn, 2005). In the brain of mice, Kojima et al. (2007) showed that RBM4 was expressed in a circadian cycling rhythm in the suprachiasmatic nucleus of the hypothalamus. This confirms earlier
Role in alternative splicing
RBM4 was shown initially to be a splicing factor. We and others have found that RBM4 is able to modulate alternative 5′-splice site and exon selection in both in vivo and in vitro splicing models (Lai et al., 2003, Lin and Tarn, 2005, Markus et al., 2006). By including or skipping alternative exons, RBM4 was able to act as both an activator and a repressor (Lai et al., 2003, Lin and Tarn, 2005, Markus et al., 2006). By showing that RBM4 binds to intronic CU-rich elements of a skeletal muscle
Biological function and relevance to disease
In Drosophila, maternally inherited RBM4 is essential for embryonic development (McNeil et al., 1999) and control of the circadian clock output pathway that determines adult eclosion (McNeil et al., 1998). RBM4 targets several RNAs involved in circadian timing, one being that for E74 (Huang et al., 2007).
Little is known at present about whether RBM4 plays a significant role in any specific biological or developmental process in mammals. One finding, however, merits closer examination. RBM4
Conclusion
RBM4 has a wide spectrum of actions in post-transcriptional processes (Fig. 2). It will now be important to obtain a more global list of RBM4 targets in order to uncover its functions and to assess the possibility that it acts in RNA operons/regulons, as has been described for other multifunctional RBPs (Keene, 2007).
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