Critical Cellular Functions and Mechanisms of Action of the RNA Helicase UAP56

Posttranscriptional processing and subcellular localization are central to the function of many RNAs and must be performed with high fidelity. The nuclear compartmentalization of RNA synthesis and processing allows maturation without interference from cytoplasmic components that may be involved in their function[1], [2]. During and after transcription, many proteins are deposited on RNA molecules to form ribonucleoproteins (RNPs) to help stabilize RNA and prevent its degradation by nucleases[3], [4], [5]. Additionally, RNP assemblies promote processing and surveillance to assess export readiness, thereby preventing the export of immature RNA6. U2AF65-associated protein 56 (UAP56; also known as DDX39B) has emerged as a key RNA helicase involved in facilitating processing steps, such as pre-mRNA splicing, and in licensing and transferring mRNPs to the export machinery for exit from the nucleus. While much of the recently published research has focused on delineating mechanisms by which UAP56 facilitates mRNA export, it has become evident that UAP56 is also essential for the export of other types of RNAs, including long non-coding RNA (lncRNA), circular RNAs, and intronless mRNA[7], [8], [9].

First identified as human leukocyte antigen-B (HLA-B) associated transcript 1 (BAT1), the 56 kDa protein UAP56 is transcribed from the MHC class III locus on chromosome 610. Due to the proximity of its gene to other immune function related genes, BAT1 (referred to as UAP56 from here on) was found to have an expression pattern similar to innate immune response factors, NFκ-B and TNF-α, and was inferred to be involved in immune modulation. Later, UAP56 was shown to be a nuclear protein with sequence similarity to the prototypic RNA helicase eukaryotic initiation factor 4A (eIF4A) and classified as a member of the DEAD-box sub-family of the helicase super family 2 (SF2)[11], [12]. Soon after, Fleckner et al. demonstrated that UAP56 interacts with U2 associated factor 65 (U2AF65; also known as U2AF2) in a manner that is essential for pre-mRNA splicing and renamed it UAP56 for this associative property13. Since then, studies in budding yeast and humans have confirmed the essential role of Sub2 (the yeast ortholog of UAP56) and UAP56, respectively, in the early steps of spliceosome assembly[14], [15], [16], [17], [18]. Additionally, UAP56 has been shown to be an RNA-stimulated ATPase and helicase, and an integral component of the cellular RNA processing and export machinery[19], [20], [21].

The human genome contains a UAP56 paralog called UAP56-related helicase 49 (URH49; also known as DDX39A) on chromosome 19 that is also present in other vertebrates but not in invertebrates such as S. cerevisiae, Drosophila, and C. elegans22. In yeast, the lethal phenotype of Sub2 deletion was shown to be rescued by UAP56 and URH49, indicating similar cellular functions for the three proteins[17], [22]. UAP56 and URH49 are expressed in most human tissues, and URH49 transcript levels was shown to be associated with changes in cell proliferation, whereas high UAP56 expression was found to be maintained throughout the cell cycle22. Both proteins share the characteristic structural and biochemical features of other helicase SF2 members and are known to be involved in aspects of RNA metabolism, including pre-mRNA splicing and mRNA export[23], [24], [25]. Recent structural analyses have revealed the central role of UAP56 and Sub2 as components of the transcription and export (TREX) complex that is comprised of several transcriptional defects of Hpr1 by overexpression (THO) subunits. UAP56 also has the capacity to interact with the export adaptor ally of AML-1 and LEF-1/RNA export factor (ALYREF; Yra1 in yeast), which is a component of the exon junction complex (EJC). Thus, UAP56 forms a bridge between TREX and EJC to enable binding of the export receptor dimer of NXF1-NXT1 (also known as TAP-p15) and licenses mRNPs for export from the nucleus[26], [27], [28], [29], [30], [31]. Other studies have demonstrated the involvement of UAP56 in the resolution of R-loops, thus contributing to the maintenance of genomic stability and the maturation of viruses within the cell[32], [33]. Finally, UAP56 expression has been reported to be altered in cancer and autoimmune diseases, and its somatic and inherited mutations have been detected in individuals with neurodevelopmental disorders[34], [35], [36], [37]. In this review, we describe the structure-activity relationship studies of UAP56 and its role as a critical RNA helicase during RNA processing, and export as well as the contributions of its activity to the maintenance of genome integrity, while drawing comparisons with URH49 and the yeast ortholog, Sub2, where appropriate. In addition, the emerging roles of UAP56 in human diseases such as multiple sclerosis and cancer, and of UAP56 mutations in neurological disorders are also discussed.

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