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      A functional human Poly(A) site requires only a potent DSE and an A-rich upstream sequence

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          Abstract

          We have analysed the sequences required for cleavage and polyadenylation in the intronless melanocortin 4 receptor (MC4R) pre-mRNA. Unlike other intronless genes, 3′end processing of the MC4R primary transcript is independent of any auxiliary sequence elements and only requires the core poly(A) sequences. Mutation of the AUUAAA hexamer had little effect on MC4R 3′end processing but small changes in the short DSE severely reduced cleavage efficiency. The MC4R poly(A) site requires only the DSE and an A-rich upstream sequence to direct efficient cleavage and polyadenylation. Our observation may be highly relevant for the understanding of how human noncanonical poly(A) sites are recognised. This is supported by a genome-wide analysis of over 10 000 poly(A) sites where we show that many human noncanonical poly(A) signals contain A-rich upstream sequences and tend to have a higher frequency of U and GU nucleotides in their DSE compared with canonical poly(A) signals. The importance of A-rich elements for noncanonical poly(A) site recognition was confirmed by mutational analysis of the human JUNB gene, which contains an A-rich noncanonical poly(A) signal.

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          A large-scale analysis of mRNA polyadenylation of human and mouse genes

          Bin Tian, Jun Hu, Haibo Zhang … (2005)
          mRNA polyadenylation is a critical cellular process in eukaryotes. It involves 3′ end cleavage of nascent mRNAs and addition of the poly(A) tail, which plays important roles in many aspects of the cellular metabolism of mRNA. The process is controlled by various cis-acting elements surrounding the cleavage site, and their binding factors. In this study, we surveyed genome regions containing cleavage sites [herein called poly(A) sites], for 13 942 human and 11 155 mouse genes. We found that a great proportion of human and mouse genes have alternative polyadenylation (∼54 and 32%, respectively). The conservation of alternative polyadenylation type or polyadenylation configuration between human and mouse orthologs is statistically significant, indicating that alternative polyadenylation is widely employed by these two species to produce alternative gene transcripts. Genes belonging to several functional groups, indicated by their Gene Ontology annotations, are biased with respect to polyadenylation configuration. Many poly(A) sites harbor multiple cleavage sites (51.25% human and 46.97% mouse sites), leading to heterogeneous 3′ end formation for transcripts. This implies that the cleavage process of polyadenylation is largely imprecise. Different types of poly(A) sites, with regard to their relative locations in a gene, are found to have distinct nucleotide composition in surrounding genomic regions. This large-scale study provides important insights into the mechanism of polyadenylation in mammalian species and represents a genomic view of the regulation of gene expression by alternative polyadenylation.
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            Molecular architecture of the human pre-mRNA 3' processing complex.

            Yongsheng Shi, Dafne Campigli Di Giammartino, Derek Taylor … (2009)
            Pre-mRNA 3' end formation is an essential step in eukaryotic gene expression. Over half of human genes produce alternatively polyadenylated mRNAs, suggesting that regulated polyadenylation is an important mechanism for posttranscriptional gene control. Although a number of mammalian mRNA 3' processing factors have been identified, the full protein composition of the 3' processing machinery has not been determined, and its structure is unknown. Here we report the purification and subsequent proteomic and structural characterization of human mRNA 3' processing complexes. Remarkably, the purified 3' processing complex contains approximately 85 proteins, including known and new core 3' processing factors and over 50 proteins that may mediate crosstalk with other processes. Electron microscopic analyses show that the core 3' processing complex has a distinct "kidney" shape and is approximately 250 A in length. Together, our data has revealed the complexity and molecular architecture of the pre-mRNA 3' processing complex.
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              Formation of mRNA 3' ends in eukaryotes: mechanism, regulation, and interrelationships with other steps in mRNA synthesis.

              J. Zhao, L. Hyman, C. Moore (1999)
              Formation of mRNA 3' ends in eukaryotes requires the interaction of transacting factors with cis-acting signal elements on the RNA precursor by two distinct mechanisms, one for the cleavage of most replication-dependent histone transcripts and the other for cleavage and polyadenylation of the majority of eukaryotic mRNAs. Most of the basic factors have now been identified, as well as some of the key protein-protein and RNA-protein interactions. This processing can be regulated by changing the levels or activity of basic factors or by using activators and repressors, many of which are components of the splicing machinery. These regulatory mechanisms act during differentiation, progression through the cell cycle, or viral infections. Recent findings suggest that the association of cleavage/polyadenylation factors with the transcriptional complex via the carboxyl-terminal domain of the RNA polymerase II (Pol II) large subunit is the means by which the cell restricts polyadenylation to Pol II transcripts. The processing of 3' ends is also important for transcription termination downstream of cleavage sites and for assembly of an export-competent mRNA. The progress of the last few years points to a remarkable coordination and cooperativity in the steps leading to the appearance of translatable mRNA in the cytoplasm.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO J
                Title: The EMBO Journal
                Publisher: Nature Publishing Group
                ISSN (Print): 0261-4189
                ISSN (Electronic): 1460-2075
                Publication date (Print): 05 May 2010
                Publication date (Electronic): 25 March 2010
                Publication date PMC-release: 25 March 2010
                Volume: 29
                Issue: 9
                Pages: 1523-1536
                Affiliations
                [1 ]simpleLaboratory of Genes and Development, Department of Biochemistry, University of Oxford , Oxford, UK
                [2 ]simpleDepartment of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School , Newark, NJ, USA
                Author notes
                [a ]Laboratory of Genes and Development, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Tel.: +44 0 1865 613 261; Fax: +44 0 1865 613 276; E-mail: andre.furger@ 123456bioch.ox.ac.uk
                Article
                Publisher Item ID: emboj201042
                DOI: 10.1038/emboj.2010.42
                PMC ID: 2876958
                PubMed ID: 20339349
                SO-VID: 9f305d59-646d-4f24-9819-dd751abcfad2
                Copyright © Copyright © 2010, European Molecular Biology Organization
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

                History
                Date received : 05 October 2009
                Date accepted : 03 March 2010
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: noncanonical poly(a) sites,intronless genes,3′end processing,melanocortin 4 receptor
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: noncanonical poly(a) sites, intronless genes, 3′end processing, melanocortin 4 receptor

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