The translational landscape of the splicing factor SRSF1 and its role in mitosis

Abstract

The shuttling serine/arginine rich (SR) protein SRSF1 (previously known as SF2/ASF) is a splicing regulator that also activates translation in the cytoplasm. In order to dissect the gene network that is translationally regulated by SRSF1, we performed a high-throughput deep sequencing analysis of polysomal fractions in cells overexpressing SRSF1. We identified approximately 1500 mRNAs that are translational targets of SRSF1. These include mRNAs encoding proteins involved in cell cycle regulation, such as spindle, kinetochore, and M phase proteins, which are essential for accurate chromosome segregation. Indeed, we show that translational activity of SRSF1 is required for normal mitotic progression. Furthermore, we found that mRNAs that display alternative splicing changes upon SRSF1 overexpression are also its translational targets, strongly suggesting that SRSF1 couples pre-mRNA splicing and translation. These data provide insights on the complex role of SRSF1 in the control of gene expression at multiple levels and its implications in cancer.DOI: http://dx.doi.org/10.7554/eLife.02028.001

SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export

“…First, SR proteins shuttle to the cytoplasm, where they are bound to spliced and polyadenylated mRNAs, are present in translating ribosomes, and regulate translation (Swartz et al 2007;Sanford et al 2008;Sato et al 2008;Änkö et al 2010;Maslon et al 2014). Second, SR proteins bind RNA with high affinity and sequence specificity (Cho et al 2011), unlike the TREX family of adaptors.…”

“…SR proteins are essential RNA-binding proteins (RBPs) with evolutionarily conserved roles as regulators of constitutive and alternative pre-mRNA splicing (Änkö 2014;Howard and Sanford 2015). SR proteins regulate such diverse processes as 3 ′ end processing (Lou et al 1998;Bradley et al 2015), mRNA export (Masuyama et al 2004;Huang and Steitz 2005), mRNP packaging (Singh et al 2012), mRNA stability (Lemaire et al 2002), and translation (Michlewski et al 2008;Maslon et al 2014). They are recruited to pre-mRNA during transcription, consistent with cotranscriptional assembly of the spliceosome and splicing (Sapra et al 2009) and suggesting that SR proteins may couple sequential events and mark mRNAs as they transit from the nucleus to the cytoplasm.…”

Regulation of alternative splicing in Drosophila by 56 RNA binding proteins

“…EIF3GA is orthologous to human EIF3G, a component of the eIF3 complex involved in translation (Lasko 2000;Hinnebusch 2006). Many splicing regulators have been shown to also affect translation (e.g., Romanelli et al 2013;Maslon et al 2014); therefore, other examples of multifunctional RNA binding proteins exist. SHEP is an RNA binding protein that contains two RRM domains, is highly expressed in the nervous system of the fly (Brown et al 2014), and is involved in gravity sensing (Armstrong et al 2006).…”

Advances in analyzing RNA diversity in eukaryotic transcriptomes: peering through the Omics lens

“…This is especially true for splice variants, which can exhibit variable coding capacities because of (i) sequence differences, (ii) altered mRNA half-lives, or (iii) differential nucleo-cytoplasmic export. Indeed, several recent efforts to measure isoform-specific translation have revealed discrete effects of 5′ end 83 , 3′ end 84 , and coding sequence 85, 86 diversity.…”