SR Proteins in Vertical Integration of Gene Expression from Transcription to RNA Processing to Translation

Abstract

Summary SR proteins have been studied extensively as a family of RNA binding proteins that participate in both constitutive and regulated pre-mRNA splicing in mammalian cells. However, SR proteins were first discovered as factors that interact with transcriptionally active chromatin. Recent studies have now uncovered properties that connect these once apparently disparate functions, showing that a subset of SR proteins seem to bind directly to the histone 3 tail, play an active role in transcriptional elongation, and co-localize with genes that are engaged in specific intra- and inter-chromosome interactions for coordinated regulation of gene expression in the nucleus. These transcription-related activities are also coupled with a further expansion of putative functions of specific SR protein family members in RNA metabolism downstream of mRNA splicing, from RNA export to stability control to translation. These findings therefore highlight the broader roles of SR proteins in vertical integration of gene expression and provide mechanistic insights into their contributions to genome stability and proper cell cycle progression in higher eukaryotic cells.

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

“…It has been shown that depletion of SRSF2 results in genomic instability; triggering significant double stranded DNA breaks [35]. In fact, SRSF2 mutations have been associated with a higher number of mutations of other genes in comparison to other spliceosomal mutations [13].…”

Frac-seq reveals isoform-specific recruitment to polyribosomes

“…This hypothesis is supported by the observation that exonic splicing enhancers can also alter the efficiency of mRNA translation in a position-specific manner Michlewski et al 2008;Delestienne et al 2010). Thus, an unanticipated consequence of alternative splicing may lie within the subsequent regulation of the RNA binding proteins packaged upon each isoform: functionally distinct mRNPs with distinct cytoplasmic fates (Zhong et al 2009;Wang et al 2012).…”

“…It is clear that the trans-acting factors associated with alternative mRNA isoforms can vary just as distinctly as the protein-coding capacities of the messages they encode. Many RNA binding proteins, including shuttling proteins, are implicated in multiple steps of posttranscriptional gene regulation, including mRNA export, stability, surveillance, localization, and translation (Sanford and Caceres 2004;Zhang and Krainer 2004;Zhong et al 2009;Han et al 2011). These factors can be transcript-associated throughout the life cycle of an mRNA and may coordinate nuclear and cytoplasmic steps of gene expression (Dreyfuss et al 2002;Nashchekin et al 2007;Kylberg et al 2008).…”

Introns in UTRs: Why we should stop ignoring them

“…However, they are also subject to splicing-dependent dephosphorylation, which promotes their tight association with the spliced mRNA. As mRNP components, SR proteins can enhance nucleocytoplasmic export, translation, and decay of their bound mRNAs [20][21][22]. Thus, as elaborated below, one means by which 5UIs and 3UIs influence gene expression is by promoting the loading of mRNP proteins with downstream functional consequences.…”