Pre-mRNA splicing and polyadenylation are critical steps in the maturation of eukaryotic mRNA. U1 snRNP is an essential component of the splicing machinery and participates in splice-site selection and spliceosome assembly by base-pairing to the 5′ splice site. U1 snRNP also plays an additional, nonsplicing global function in 3′ end mRNA processing; it actively suppresses the polyadenylation machinery from using early, mostly intronic polyadenylation signals which would lead to aberrant, truncated mRNAs. Thus, U1 snRNP safeguards pre-mRNA transcripts against premature polyadenylation and contributes to the regulation of alternative polyadenylation. Here, we review the role of U1 snRNP in 3′ end mRNA processing, outline the evidence that led to the recognition of its physiological, general role in inhibiting polyadenylation, and finally highlight the possibility of manipulating this U1 snRNP function for therapeutic purposes in cancer. 1. Introduction The generation of translationally competent messenger RNAs (mRNAs) is a complex molecular process that involves distinctive enzymatic reactions and dedicated cellular machineries that result in the splicing, capping, editing, and polyadenylation of a pre-mRNA transcript. During this process, the choice and usage of splice sites (alternative splicing, AS) and of polyadenylation signals (alternative polyadenylation, APA) within a common pre-mRNA can be differentially regulated depending on the developmental state, tissue, and cell type or in response to a variety of physiological stimuli or pathological conditions [1, 2]. Collectively, alternative splicing and polyadenylation are key molecular mechanisms for increasing the functional diversity of the human proteome, allowing the relatively small human genome (<25,000 genes) to generate an excess of 100,000 different protein isoforms [3]. However, because of the pervasiveness and essential role of AS in all physiological processes, aberrant RNA processing is also frequently associated with many diseases [4], and both AS and APA are deregulated and exploited by cancer cells to promote their growth and survival [5–7]. This review will focus on the recently described splicing-independent functions of U1 small ribonucleoprotein particle (snRNP) in pre-mRNA processing, with emphasis on its role in the regulation of APA site selection and in the suppression of intronic polyadenylation (IPA). Furthermore, we will address innovative approaches to leverage U1 snRNP functions as therapeutic avenues in cancer treatment. 2. U1 snRNP Canonical Role in Splicing: A Harbinger
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