The long and the short of it: The role of the zinc finger polyadenosine RNA binding protein, Nab2, in control of poly(A) tail length

Proper gene expression in eukaryotic cells requires the production of properly processed mRNA transcripts in the nucleus and export of those transcripts to the cytoplasm for translation. Following transcription by RNA polymerase II (RNAP II), nascent mRNA transcripts undergo a series of co-transcriptional processing steps to reach maturity. Specifically, mRNA transcripts are bound by processing factors that perform 5′-end capping to add a 7-methylguanosine cap, splicing to remove introns, and 3′-end cleavage and polyadenylation to add a polyadenosine (poly(A)) tail (1,2). Transcripts that are improperly processed and could lead to the production of deleterious proteins are recognized and destroyed by mRNA surveillance factors (3–5). Following nuclear processing, mRNA transcripts are exported through nuclear pore complexes (NPCs) to the cytoplasm where they can be translated (6–8). Throughout their lifespan, mRNA transcripts interface with RNA binding proteins that regulate the processing, export, translation, and degradation of these mRNAs. Importantly, the mechanisms and factors required for mRNA processing and export are evolutionarily conserved from yeast to humans. Thus, experiments in the yeast model system have contributed significantly to our understanding of mRNA processing and export in higher eukaryotes. Synthesis of poly(A) tails of the right length by the 3′-end processing and polyadenylation machinery is a particularly critical step in eukaryotic gene expression. In yeast and metazoans, poly(A) RNA binding proteins (Pabs) play a key role in regulating poly(A) tail length (9). Most Pabs bind specifically to the polyadenosine RNA via an RNA recognition motif (RRM); however, S. cerevisiae Nab2 (nuclear abundant poly(A) RNA binding protein) binds specifically to polyadenosine RNA via a CCCH-type zinc finger domain (10). Nab2 is therefore the founding member of a novel class of zinc finger Pabs (11). Critically, mutations in genes encoding ubiquitously expressed Pabs cause human disease. Mutations in the gene encoding the nuclear RRM-containing Pab, PABPN1, cause oculopharyngeal muscular dystrophy (OPMD), while mutations in the gene encoding the human Nab2 homologue, ZC3H14, cause a form of autosomal recessive intellectual disability (ARID) (12,13). Proper Pab function and regulation of poly(A) tail length is therefore critical for tissue-specific functions. As the length of the poly(A) tail impacts the stability, nuclear export, and translation of mRNA transcripts, regulation of poly(A) tail length can control the fate of transcripts. In the yeast Saccharomyces cerevisiae, the average length of poly(A) tails on polyadenylated RNA transcripts is ~60–80 adenosines, whereas in mammalian cells, the average length is approximately 250 adenosines (9). Although shorter than normal poly(A) tails are correlated with decreased RNA stability and translation (14–18), the consequences of longer than normal tails are unknown. A thorough understanding of poly(A) tail length control thus requires identification of the main protein factors that affect poly(A) tail length and elucidation of mechanism by which these factors alter poly(A) tail length. The topic of poly(A) tail length control by RRM-containing Pabs has recently been reviewed (9,19). Here, we focus primarily on the role of the nuclear zinc finger Pab, Nab2, in the control of poly(A) tail length in S. cerevisiae. Importantly, key aspects of our current understanding of poly(A) tail length control have come from in vitro cleavage and polyadenylation assays using yeast lysate coupled with functional studies of S. cerevisiae mutants. We discuss the function of Nab2 and speculate on the potential mechanisms by which Nab2 could modulate 3′-end processing and the polyadenylation machinery to control poly(A) tail length based on the physical and genetic interactions of Nab2. We also discuss the function of the Drosophila Nab2 counterpart, dNab2, and the human Nab2 counterpart, ZC3H14. Given that mutations in ZC3H14 cause a form of intellectual disability (12), we comment on how defects in the function of a ubiquitously expressed Pab, ZC3H14, could lead to neurological defects in humans.