Cleavage and polyadenylation: Ending the message expands gene regulation

ABSTRACT Cleavage and polyadenylation (pA) is a fundamental step that is required for the maturation of primary protein encoding transcripts into functional mRNAs that can be exported from the nucleus and translated in the cytoplasm. 3′end processing is dependent on the assembly of a multiprotein processing complex on the pA signals that reside in the pre-mRNAs. Most eukaryotic genes have multiple pA signals, resulting in alternative cleavage and polyadenylation (APA), a widespread phenomenon that is important to establish cell state and cell type specific transcriptomes. Here, we review how pA sites are recognized and comprehensively summarize how APA is regulated and creates mRNA isoform profiles that are characteristic for cell types, tissues, cellular states and disease.

[1]  Charlotte Kuperwasser,et al.  Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer , 2016, eLife.

[2]  M. Bushell,et al.  Polypyrimidine-tract-binding protein: a multifunctional RNA-binding protein. , 2008, Biochemical Society transactions.

[3]  S. Goldenberg,et al.  Polysome profiling shows extensive posttranscriptional regulation during human adipocyte stem cell differentiation into adipocytes. , 2013, Stem cell research.

[4]  J. Li,et al.  Tandem alternative polyadenylation events of genes in non-eosinophilic nasal polyp tissue identified by high-throughput sequencing analysis , 2014, International journal of molecular medicine.

[5]  M. Hengartner,et al.  Analysis of C. elegans intestinal gene expression and polyadenylation by fluorescence-activated nuclei sorting and 3′-end-seq , 2012, Nucleic acids research.

[6]  Y. Ohkawa,et al.  Human TREX component Thoc5 affects alternative polyadenylation site choice by recruiting mammalian cleavage factor I , 2013, Nucleic acids research.

[7]  J. Manley,et al.  The Polyadenylation Factor CstF-64 Regulates Alternative Processing of IgM Heavy Chain Pre-mRNA during B Cell Differentiation , 1996, Cell.

[8]  A. Furger,et al.  Alternative polyadenylation: less than meets the eye? , 2014, Biochemical Society transactions.

[9]  W. Boelens,et al.  The human U1A snRNP protein regulates polyadenylation via a direct interaction with poly(A) polymerase , 1994, Cell.

[10]  E. Wahle.  A novel poly(A)-binding protein acts as a specificity factor in the second phase of messenger RNA polyadenylation , 1991, Cell.

[11]  L. C. Hinske,et al.  In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing , 2013, Acta Neuropathologica.

[12]  W. Keller,et al.  Purification and Characterization of Human Cleavage Factor I Involved in the 3′ End Processing of Messenger RNA Precursors (*) , 1996, The Journal of Biological Chemistry.

[13]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[14]  Adrian Wiestner,et al.  Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. , 2007, Blood.

[15]  G. Sobue,et al.  Position-specific binding of FUS to nascent RNA regulates mRNA length , 2015, Genes & development.

[16]  A. Sachs,et al.  Poly(A) Tail Length Control in Saccharomyces cerevisiae Occurs by Message-Specific Deadenylation , 1998, Molecular and Cellular Biology.

[17]  J. Nevins,et al.  An ordered pathway of assembly of components required for polyadenylation site recognition and processing. , 1989, Genes & development.

[18]  S. West,et al.  Splicing-coupled 3′ end formation requires a terminal splice acceptor site, but not intron excision , 2013, Nucleic acids research.

[19]  E. Wang,et al.  Analysis and design of RNA sequencing experiments for identifying isoform regulation , 2010, Nature Methods.

[20]  F. Iborra,et al.  α-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes , 2010, Nucleic acids research.

[21]  C. Mayhew,et al.  HSF1 Modulation of Hsp70 mRNA Polyadenylation via Interaction with Symplekin* , 2004, Journal of Biological Chemistry.

[22]  B. Tian,et al.  Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development , 2009, Proceedings of the National Academy of Sciences.

[23]  David Baltimore,et al.  Synthesis of secreted and membrane-bound immunoglobulin mu heavy chains is directed by mRNAs that differ at their 3′ ends , 1980, Cell.

[24]  Hanno Langen,et al.  Direct interactions between subunits of CPSF and the U2 snRNP contribute to the coupling of pre-mRNA 3' end processing and splicing. , 2006, Molecular cell.

[25]  W. Zwart,et al.  Supplementary Materials and Methods , 2013 .

[26]  P. Moll,et al.  QuantSeq 3[prime] mRNA sequencing for RNA quantification , 2014 .

[27]  P. Bork,et al.  Splicing factors stimulate polyadenylation via USEs at non‐canonical 3′ end formation signals , 2007, The EMBO journal.

[28]  N. Proudfoot,et al.  Transcriptional Termination Enhances Protein Expression in Human Cells , 2009, Molecular cell.

[29]  Tala Bakheet,et al.  ARED 3.0: the large and diverse AU-rich transcriptome , 2005, Nucleic Acids Res..

[30]  T. Shenk,et al.  The sequence 5′-AAUAAA-3′ forms part of the recognition site for polyadenylation of late SV40 mRNAs , 1981, Cell.

[31]  N. Proudfoot,et al.  Alpha‐thalassaemia caused by a poly(A) site mutation reveals that transcriptional termination is linked to 3′ end processing in the human alpha 2 globin gene. , 1986, The EMBO journal.

[32]  E. Wahle.  Purification and characterization of a mammalian polyadenylate polymerase involved in the 3' end processing of messenger RNA precursors. , 1991, The Journal of biological chemistry.

[33]  Hongde Liu,et al.  The nucleosome regulates the usage of polyadenylation sites in the human genome , 2013, BMC Genomics.

[34]  A. Corbett,et al.  Loss of nuclear poly(A)-binding protein 1 causes defects in myogenesis and mRNA biogenesis. , 2010, Human molecular genetics.

[35]  W. Marzluff,et al.  Introns in histone genes alter the distribution of 3' ends. , 1990, Nucleic acids research.

[36]  Wencheng Li,et al.  PAF Complex Plays Novel Subunit-Specific Roles in Alternative Cleavage and Polyadenylation , 2016, PLoS genetics.

[37]  P. Bohjanen,et al.  Analysis of CUGBP1 Targets Identifies GU-Repeat Sequences That Mediate Rapid mRNA Decay , 2010, Molecular and Cellular Biology.

[38]  Angela L. Morrison,et al.  Nucleophosmin deposition during mRNA 3′ end processing influences poly(A) tail length , 2011, The EMBO journal.

[39]  J. Majewski,et al.  Polyadenylation-Dependent Control of Long Noncoding RNA Expression by the Poly(A)-Binding Protein Nuclear 1 , 2012, PLoS genetics.

[40]  G. Carmichael,et al.  Alu element‐mediated gene silencing , 2008, The EMBO journal.

[41]  Bin Tian,et al.  A large-scale analysis of mRNA polyadenylation of human and mouse genes , 2005, Nucleic acids research.

[42]  Bin Tian,et al.  Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control , 2016, BMC Biology.

[43]  J. Manley,et al.  RNA recognition by the human polyadenylation factor CstF , 1997, Molecular and cellular biology.

[44]  S. Orkin,et al.  Thalassemia due to a mutation in the cleavage‐polyadenylation signal of the human beta‐globin gene. , 1985, The EMBO journal.

[45]  A. Furger,et al.  Regulation of transcription termination in the nematode Caenorhabditis elegans , 2009, Nucleic acids research.

[46]  Toru Yamashita,et al.  Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology , 2012, Nature Communications.

[47]  Jie Li,et al.  APASdb: a database describing alternative poly(A) sites and selection of heterogeneous cleavage sites downstream of poly(A) signals , 2014, Nucleic Acids Res..

[48]  Niseema D. Pachikara,et al.  U1A Inhibits Cleavage at the Immunoglobulin M Heavy-Chain Secretory Poly(A) Site by Binding between the Two Downstream GU-Rich Regions , 2004, Molecular and Cellular Biology.

[49]  M. Hentze,et al.  The prothrombin 3'end formation signal reveals a unique architecture that is sensitive to thrombophilic gain-of-function mutations. , 2004, Blood.

[50]  Larry N. Singh,et al.  U1 snRNP Determines mRNA Length and Regulates Isoform Expression , 2012, Cell.

[51]  G. Christofori,et al.  Cleavage and polyadenylation factor CPF specifically interacts with the pre‐mRNA 3′ processing signal AAUAAA. , 1991, The EMBO journal.

[52]  E. Wahle,et al.  Assembly of a processive messenger RNA polyadenylation complex. , 1993, The EMBO journal.

[53]  William Ritchie,et al.  Differential Repression of Alternative Transcripts: A Screen for miRNA Targets , 2006, PLoS Comput. Biol..

[54]  Rachel B. Brem,et al.  Noncanonical transcript forms in yeast and their regulation during environmental stress. , 2010, RNA.

[55]  D. Bentley,et al.  Coordination of RNA Polymerase II Pausing and 3′ End Processing Factor Recruitment with Alternative Polyadenylation , 2015, Molecular and Cellular Biology.

[56]  S. Gregory,et al.  Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. , 2013, RNA.

[57]  L. Tong,et al.  Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease , 2006, Nature.

[58]  Mihaela Zavolan,et al.  Genome-wide analysis of pre-mRNA 3' end processing reveals a decisive role of human cleavage factor I in the regulation of 3' UTR length. , 2012, Cell reports.

[59]  J. Wilusz,et al.  DSEF-1 is a member of the hnRNP H family of RNA-binding proteins and stimulates pre-mRNA cleavage and polyadenylation in vitro. , 1998, Nucleic acids research.

[60]  Chong-Jian Chen,et al.  Differential genome-wide profiling of tandem 3' UTRs among human breast cancer and normal cells by high-throughput sequencing. , 2011, Genome research.

[61]  P. Fortes,et al.  Participation of the nuclear cap binding complex in pre-mRNA 3' processing. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[62]  J. Steitz,et al.  Widespread Inducible Transcription Downstream of Human Genes. , 2015, Molecular cell.

[63]  D. Gautheret,et al.  Conservation of alternative polyadenylation patterns in mammalian genes , 2006, BMC Genomics.

[64]  K. Khabar,et al.  Alternative polyadenylation variants of the RNA binding protein, HuR: abundance, role of AU-rich elements and auto-Regulation , 2009, Nucleic acids research.

[65]  S. Schwartz,et al.  A Downstream Polyadenylation Element in Human Papillomavirus Type 16 L2 Encodes Multiple GGG Motifs and Interacts with hnRNP H , 2005, Journal of Virology.

[66]  C. Burge,et al.  Most mammalian mRNAs are conserved targets of microRNAs. , 2008, Genome research.

[67]  M. Rosbash,et al.  A block to mRNA nuclear export in S. cerevisiae leads to hyperadenylation of transcripts that accumulate at the site of transcription. , 2001, Molecular cell.

[68]  Eric T. Wang,et al.  Distal Alternative Last Exons Localize mRNAs to Neural Projections. , 2016, Molecular cell.

[69]  C. Baker,et al.  Sequences homologous to 5' splice sites are required for the inhibitory activity of papillomavirus late 3' untranslated regions , 1994, Molecular and cellular biology.

[70]  J. Yates,et al.  Molecular architecture of the human pre-mRNA 3' processing complex. , 2009, Molecular cell.

[71]  Bin Tian,et al.  Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA , 2016, Cell Discovery.

[72]  Sang-Ho Chung,et al.  Embryonic Lethal Abnormal Vision-Like RNA-Binding Proteins Regulate Neurite Outgrowth and Tau Expression in PC12 Cells , 1999, The Journal of Neuroscience.

[73]  R. Krug,et al.  Influenza A virus NS1 protein targetspoly(A)‐binding protein II of the cellular 3′‐end processing machinery , 1999, The EMBO journal.

[74]  J. Manley,et al.  Transcriptional activators enhance polyadenylation of mRNA precursors , 2011, RNA biology.

[75]  J. Alwine,et al.  Elements upstream of the AAUAAA within the human immunodeficiency virus polyadenylation signal are required for efficient polyadenylation in vitro , 1992, Molecular and cellular biology.

[76]  J. Rommens,et al.  Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy , 1998, Nature Genetics.

[77]  P. Kapranov,et al.  Comprehensive Polyadenylation Site Maps in Yeast and Human Reveal Pervasive Alternative Polyadenylation , 2010, Cell.

[78]  Matthias W. Hentze,et al.  Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia , 2001, Nature Genetics.

[79]  Michael R. Green,et al.  Global Promotion of Alternative Internal Exon Usage by mRNA 3' End Formation Factors. , 2015, Molecular cell.

[80]  G. M. Wilson,et al.  Cleavage and polyadenylation specificity factor 30: An RNA-binding zinc-finger protein with an unexpected 2Fe–2S cluster , 2016, Proceedings of the National Academy of Sciences.

[81]  J. Alwine,et al.  Definition of the upstream efficiency element of the simian virus 40 late polyadenylation signal by using in vitro analyses , 1992, Molecular and cellular biology.

[82]  Wei Li,et al.  CFIm25 links Alternative Polyadenylation to Glioblastoma Tumor Suppression , 2014, Nature.

[83]  Xin Hu,et al.  The 3′UTR signature defines a highly metastatic subgroup of triple-negative breast cancer , 2016, Oncotarget.

[84]  B. Graveley,et al.  CPSF recognition of an HIV-1 mRNA 3'-processing enhancer: multiple sequence contacts involved in poly(A) site definition. , 1995, Genes & development.

[85]  L. Steinmetz,et al.  Alternative polyadenylation diversifies post‐transcriptional regulation by selective RNA–protein interactions , 2014, Molecular Systems Biology.

[86]  T. Gradus,et al.  Localized Regulation of Axonal RanGTPase Controls Retrograde Injury Signaling in Peripheral Nerve , 2008, Neuron.

[87]  D. Geschwind,et al.  Subcellular Knockout of Importin β1 Perturbs Axonal Retrograde Signaling , 2012, Neuron.

[88]  J. Goeman,et al.  Poly(A) binding protein nuclear 1 levels affect alternative polyadenylation , 2012, Nucleic acids research.

[89]  Larry N. Singh,et al.  U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation , 2010, Nature.

[90]  C. Moore,et al.  Two proteins crosslinked to RNA containing the adenovirus L3 poly(A) site require the AAUAAA sequence for binding. , 1988, The EMBO journal.

[91]  Pedro G. Ferreira,et al.  Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing , 2016, Scientific Reports.

[92]  H. Lou,et al.  Regulation of Alternative Polyadenylation by U1 snRNPs and SRp20 , 1998, Molecular and Cellular Biology.

[93]  M. Wolfe,et al.  Alternative polyadenylation and miR‐34 family members regulate tau expression , 2013, Journal of neurochemistry.

[94]  Rahul C. Deo,et al.  Recognition of Polyadenylate RNA by the Poly(A)-Binding Protein , 1999, Cell.

[95]  A. Furger,et al.  Two G-Rich Regulatory Elements Located Adjacent to and 440 Nucleotides Downstream of the Core Poly(A) Site of the Intronless Melanocortin Receptor 1 Gene Are Critical for Efficient 3′ End Processing , 2006, Molecular and Cellular Biology.

[96]  W. Marzluff,et al.  A core complex of CPSF73, CPSF100, and Symplekin may form two different cleavage factors for processing of poly(A) and histone mRNAs. , 2009, Molecular cell.

[97]  H. Martinson,et al.  Assembly of the Cleavage and Polyadenylation Apparatus Requires About 10 Seconds In Vivo and Is Faster for Strong than for Weak Poly(A) Sites , 1999, Molecular and Cellular Biology.

[98]  R. Elkon,et al.  Alternative cleavage and polyadenylation: extent, regulation and function , 2013, Nature Reviews Genetics.

[99]  Jing Zhao,et al.  Formation of mRNA 3′ Ends in Eukaryotes: Mechanism, Regulation, and Interrelationships with Other Steps in mRNA Synthesis , 1999, Microbiology and Molecular Biology Reviews.

[100]  D. Cooper,et al.  A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes I: general principles and overview , 2006, Human Genetics.

[101]  W. Keller,et al.  Human Fip1 is a subunit of CPSF that binds to U‐rich RNA elements and stimulates poly(A) polymerase , 2004, The EMBO journal.

[102]  J. Nevins,et al.  Molecular analyses of two poly(A) site-processing factors that determine the recognition and efficiency of cleavage of the pre-mRNA , 1991, Molecular and cellular biology.

[103]  Yi Li,et al.  Poly(A) code analyses reveal key determinants for tissue-specific mRNA alternative polyadenylation , 2016, RNA.

[104]  Wencheng Li,et al.  RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs , 2014, Genes & development.

[105]  Jeffrey Wilusz,et al.  Upstream Elements Present in the 3′-Untranslated Region of Collagen Genes Influence the Processing Efficiency of Overlapping Polyadenylation Signals* , 2002, The Journal of Biological Chemistry.

[106]  R. Desnick,et al.  Fabry disease: novel alpha-galactosidase A 3'-terminal mutations result in multiple transcripts due to aberrant 3'-end formation. , 2003, American journal of human genetics.

[107]  Wei Li,et al.  NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation , 2015, eLife.

[108]  P. Bohjanen,et al.  Perspectives on the ARE as it turns 25 years old , 2012, Wiley interdisciplinary reviews. RNA.

[109]  Craig Montell,et al.  Inhibition of RNA cleavage but not polyadenylation by a point mutation in mRNA 3′ consensus sequence AAUAAA , 1983, Nature.

[110]  H. Aburatani,et al.  Regulation of alternative polyadenylation by Nkx2-5 and Xrn2 during mouse heart development , 2016, eLife.

[111]  Sylvie Doublié,et al.  Crystal structure of a human cleavage factor CFI(m)25/CFI(m)68/RNA complex provides an insight into poly(A) site recognition and RNA looping. , 2011, Structure.

[112]  Reiner Schulz,et al.  Regulation of alternative polyadenylation by genomic imprinting. , 2008, Genes & development.

[113]  D. Hovorun,et al.  Downstream elements of mammalian pre-mRNA polyadenylation signals: primary, secondary and higher-order structures. , 2003, Nucleic acids research.

[114]  Hans D. Ochs,et al.  A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA→AAUGAA) leads to the IPEX syndrome , 2001, Immunogenetics.

[115]  Kevin Struhl,et al.  Global Analysis of mRNA Isoform Half-Lives Reveals Stabilizing and Destabilizing Elements in Yeast , 2014, Cell.

[116]  M. Wollerton,et al.  The upstream sequence element of the C2 complement poly(A) signal activates mRNA 3' end formation by two distinct mechanisms. , 1998, Genes & development.

[117]  B. Tian,et al.  Bioinformatic identification of candidate cis-regulatory elements involved in human mRNA polyadenylation. , 2005, RNA.

[118]  S. Doublié,et al.  The structure of human Cleavage Factor Im hints at functions beyond UGUA-specific RNA binding , 2011 .

[119]  The roles of microRNAs in the regulation of tumor metastasis , 2015, Cell & Bioscience.

[120]  J. Manley,et al.  Four factors are required for 3'-end cleavage of pre-mRNAs. , 1989, Genes & development.

[121]  Ralf Schmidt,et al.  A comprehensive analysis of 3′ end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogeneous ribonucleoprotein C on cleavage and polyadenylation , 2015, bioRxiv.

[122]  Alexander W. Emch,et al.  Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus. , 2013, Cell reports.

[123]  Alka A. Potdar,et al.  Coding Region Polyadenylation Generates a Truncated tRNA Synthetase that Counters Translation Repression , 2012, Cell.

[124]  W. Keller,et al.  The WD‐repeat protein Pfs2p bridges two essential factors within the yeast pre‐mRNA 3′‐end‐processing complex , 2000, The EMBO journal.

[125]  P. Scheiffele,et al.  Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation , 2012, PLoS biology.

[126]  Christopher Y. Park,et al.  PAPERCLIP Identifies MicroRNA Targets and a Role of CstF64/64tau in Promoting Non-canonical poly(A) Site Usage. , 2016, Cell reports.

[127]  T. Babak,et al.  A quantitative atlas of polyadenylation in five mammals , 2012, Genome research.

[128]  E. Wahle,et al.  Isolation and expression of cDNA clones encoding mammalian poly(A) polymerase. , 1991, The EMBO journal.

[129]  E. Wagner,et al.  A CPSF-73 Homologue Is Required for Cell Cycle Progression but Not Cell Growth and Interacts with a Protein Having Features of CPSF-100 , 2005, Molecular and Cellular Biology.

[130]  M. Hentze,et al.  3′ end mRNA processing: molecular mechanisms and implications for health and disease , 2008, The EMBO journal.

[131]  J. Manley,et al.  The RNA polymerase II CTD coordinates transcription and RNA processing. , 2012, Genes & development.

[132]  Jeffrey Wilusz,et al.  Downstream sequence elements with different affinities for the hnRNP H/H' protein influence the processing efficiency of mammalian polyadenylation signals. , 2002, Nucleic acids research.

[133]  Rei-Lin Kuo,et al.  The CPSF30 Binding Site on the NS1A Protein of Influenza A Virus Is a Potential Antiviral Target , 2006, Journal of Virology.

[134]  Yongsheng Shi,et al.  Alternative polyadenylation: new insights from global analyses. , 2012, RNA.

[135]  Ji Wan,et al.  Transcriptome-wide analyses of CstF64–RNA interactions in global regulation of mRNA alternative polyadenylation , 2012, Proceedings of the National Academy of Sciences.

[136]  H. Lilie,et al.  Stimulation of poly(A) polymerase through a direct interaction with the nuclear poly(A) binding protein allosterically regulated by RNA , 2003, The EMBO journal.

[137]  J. Manley,et al.  RNA polymerase II is an essential mRNA polyadenylation factor , 1998, Nature.

[138]  S. Doublié,et al.  The structure of human cleavage factor I(m) hints at functions beyond UGUA-specific RNA binding: a role in alternative polyadenylation and a potential link to 5' capping and splicing. , 2011, RNA biology.

[139]  S. Berget,et al.  Mutation of the AAUAAA polyadenylation signal depresses in vitro splicing of proximal but not distal introns. , 1991, Genes & development.

[140]  D. Bartel,et al.  Formation, Regulation and Evolution of Caenorhabditis elegans 3′UTRs , 2010, Nature.

[141]  Jeong-Hwa Lee,et al.  hnRNP L binds to CA repeats in the 3'UTR of bcl-2 mRNA. , 2009, Biochemical and biophysical research communications.

[142]  Tolga Can,et al.  Estrogen-induced upregulation and 3′-UTR shortening of CDC6 , 2012, Nucleic acids research.

[143]  Vicent Pelechano,et al.  Single-cell polyadenylation site mapping reveals 3′ isoform choice variability , 2015, Molecular systems biology.

[144]  R. Elkon,et al.  Alternative Cleavage and Polyadenylation during Colorectal Cancer Development , 2012, Clinical Cancer Research.

[145]  Steven W. Flavell,et al.  Genome-Wide Analysis of MEF2 Transcriptional Program Reveals Synaptic Target Genes and Neuronal Activity-Dependent Polyadenylation Site Selection , 2008, Neuron.

[146]  I. Mattaj,et al.  The carboxyl terminus of vertebrate poly(A) polymerase interacts with U2AF 65 to couple 3'-end processing and splicing. , 2000, Genes & development.

[147]  L. Maquat,et al.  Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. , 2005, Current opinion in cell biology.

[148]  Markus Landthaler,et al.  Cold-induced RNA-binding proteins regulate circadian gene expression by controlling alternative polyadenylation , 2013, Scientific Reports.

[149]  E. Wahle,et al.  Poly(A) Tail Length Is Controlled by the Nuclear Poly(A)-binding Protein Regulating the Interaction between Poly(A) Polymerase and the Cleavage and Polyadenylation Specificity Factor* , 2009, The Journal of Biological Chemistry.

[150]  J. Manley,et al.  A polyadenylation factor subunit is the human homologue of theDrosophila suppressor of forked protein , 1994, Nature.

[151]  Wencheng Li,et al.  Mediator complex regulates alternative mRNA processing via the MED23 subunit. , 2012, Molecular cell.

[152]  D. Schümperli,et al.  Cycling in the nucleus: regulation of RNA 3' processing and nuclear organization of replication-dependent histone genes. , 2016, Current opinion in cell biology.

[153]  D. Du,et al.  RNA Polyadenylation Sites on the Genomes of Microorganisms, Animals, and Plants , 2013, PloS one.

[154]  S. Liebhaber,et al.  αCP Poly(C) Binding Proteins Act as Global Regulators of Alternative Polyadenylation , 2013, Molecular and Cellular Biology.

[155]  Emmette R. Hutchison,et al.  miR-375 Inhibits Differentiation of Neurites by Lowering HuD Levels , 2010, Molecular and Cellular Biology.

[156]  K. Struhl,et al.  Species-specific factors mediate extensive heterogeneity of mRNA 3′ ends in yeasts , 2013, Proceedings of the National Academy of Sciences.

[157]  N. Proudfoot,et al.  Terminal exon definition occurs cotranscriptionally and promotes termination of RNA polymerase II. , 1999, Molecular cell.

[158]  M. Wickens,et al.  Role of the conserved AAUAAA sequence: four AAUAAA point mutants prevent messenger RNA 3' end formation. , 1984, Science.

[159]  D. Gautheret,et al.  Patterns of variant polyadenylation signal usage in human genes. , 2000, Genome research.

[160]  John R Yates,et al.  CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3′ processing , 2014, Genes & development.

[161]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[162]  T. Hohn,et al.  The contribution of AAUAAA and the upstream element UUUGUA to the efficiency of mRNA 3′‐end formation in plants. , 1994, The EMBO journal.

[163]  Tomaz Curk,et al.  SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export , 2016, Genes & development.

[164]  A. Kakita,et al.  Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43 , 2016, Nucleic acids research.

[165]  J. Manley,et al.  Primary structure and expression of bovine poly(A) polymerase , 1991, Nature.

[166]  L. Ohno-Machado,et al.  Alternative Polyadenylation Allows Differential Negative Feedback of Human miRNA miR-579 on Its Host Gene ZFR , 2015, PloS one.

[167]  D. Bentley,et al.  Capping, splicing, and 3' processing are independently stimulated by RNA polymerase II: different functions for different segments of the CTD. , 2001, Genes & development.

[168]  Xiaohui S. Xie,et al.  Fip1 regulates mRNA alternative polyadenylation to promote stem cell self‐renewal , 2014, The EMBO journal.

[169]  W. Keller,et al.  Human pre‐mRNA cleavage factor IIm contains homologs of yeast proteins and bridges two other cleavage factors , 2000, The EMBO journal.

[170]  Liang Tong,et al.  Crystal structure of murine CstF-77: dimeric association and implications for polyadenylation of mRNA precursors. , 2007, Molecular cell.

[171]  Sylvain Egloff,et al.  The pol II CTD: new twists in the tail , 2016, Nature Structural &Molecular Biology.

[172]  Xiang-Dong Fu,et al.  A multiplex RNA-seq strategy to profile poly(A+) RNA: application to analysis of transcription response and 3' end formation. , 2011, Genomics.

[173]  V. Beneš,et al.  The differential expression of alternatively polyadenylated transcripts is a common stress-induced response mechanism that modulates mammalian mRNA expression in a quantitative and qualitative fashion , 2016, RNA.

[174]  Gabriele Varani,et al.  Recognition of GU‐rich polyadenylation regulatory elements by human CstF‐64 protein , 2003, The EMBO journal.

[175]  C. Brokamp,et al.  Coordinated Post-transcriptional Regulation of Hsp70.3 Gene Expression by MicroRNA and Alternative Polyadenylation* , 2011, The Journal of Biological Chemistry.

[176]  J. Manley,et al.  The BARD1-CstF-50 Interaction Links mRNA 3′ End Formation to DNA Damage and Tumor Suppression , 2001, Cell.

[177]  W. Keller,et al.  An interaction between U2AF 65 and CF Im links the splicing and 3′ end processing machineries , 2006, The EMBO journal.

[178]  T. Jensen,et al.  Nuclear mRNA surveillance in THO/sub2 mutants is triggered by inefficient polyadenylation. , 2008, Molecular cell.

[179]  Chaolin Zhang,et al.  Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. , 2014, Molecular cell.

[180]  C. Glatt,et al.  Anxiety-associated alternative polyadenylation of the serotonin transporter mRNA confers translational regulation by hnRNPK , 2013, Proceedings of the National Academy of Sciences.

[181]  S. J. Coleman,et al.  Determinants and implications of mRNA poly(A) tail size--does this protein make my tail look big? , 2014, Seminars in cell & developmental biology.

[182]  Hiroshi Handa,et al.  Evidence that cleavage factor Im is a heterotetrameric protein complex controlling alternative polyadenylation , 2010, Genes to cells : devoted to molecular & cellular mechanisms.

[183]  J. Steitz,et al.  Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3′‐end maturation , 2008, EMBO reports.

[184]  M. Simonelig.  PABPN1 shuts down alternative poly(A) sites , 2012, Cell Research.

[185]  Kirk M Brown,et al.  A mechanism for the regulation of pre-mRNA 3' processing by human cleavage factor Im. , 2003, Molecular cell.

[186]  C. Sunkel,et al.  RNA polymerase II kinetics in polo polyadenylation signal selection , 2011, The EMBO journal.

[187]  Tom H. Cheung,et al.  Alternative polyadenylation mediates microRNA regulation of muscle stem cell function. , 2012, Cell stem cell.

[188]  M. Zavolan,et al.  Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33 , 2014, Genes & development.

[189]  Andreas R. Gruber,et al.  Cleavage factor Im is a key regulator of 3′ UTR length , 2012, RNA biology.

[190]  A. Riccio,et al.  To localize or not to localize: mRNA fate is in 3'UTR ends. , 2009, Trends in cell biology.

[191]  E. van Nimwegen,et al.  Global 3′ UTR shortening has a limited effect on protein abundance in proliferating T cells , 2014, Nature Communications.

[192]  Wencheng Li,et al.  The Conserved Intronic Cleavage and Polyadenylation Site of CstF-77 Gene Imparts Control of 3′ End Processing Activity through Feedback Autoregulation and by U1 snRNP , 2013, PLoS genetics.

[193]  G. Yehia,et al.  Analysis of alterative cleavage and polyadenylation by 3′ region extraction and deep sequencing , 2012, Nature Methods.

[194]  Mihaela Zavolan,et al.  Genome-wide Analysis of Pre-mRNA 3 0 End Processing Reveals a Decisive Role of Human Cleavage Factor I in the Regulation of 3 0 UTR Length , 2012 .

[195]  L. Minvielle-Sebastia,et al.  Hexameric architecture of CstF supported by CstF-50 homodimerization domain structure. , 2011, RNA.

[196]  P. Sharp,et al.  Proliferating Cells Express mRNAs with Shortened 3' Untranslated Regions and Fewer MicroRNA Target Sites , 2008, Science.

[197]  Christian A. Ross,et al.  Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS , 2015, Nature Neuroscience.

[198]  A. Furger,et al.  Stem-loop 1 of the U1 snRNP plays a critical role in the suppression of HIV-1 polyadenylation. , 2000, RNA.

[199]  Reuven Agami,et al.  Transcription initiation determines its end. , 2015, Molecular cell.

[200]  C. Milcarek,et al.  The hnRNPs F and H2 bind to similar sequences to influence gene expression. , 2006, The Biochemical journal.

[201]  James B. Brown,et al.  Global patterns of tissue-specific alternative polyadenylation in Drosophila. , 2012, Cell reports.

[202]  B. Blencowe,et al.  SRm160 Splicing Coactivator Promotes Transcript 3′-End Cleavage , 2002, Molecular and Cellular Biology.

[203]  Jørgen Kjems,et al.  Crosstalk between mRNA 3' end processing and transcription initiation. , 2010, Molecular cell.

[204]  R. Yi,et al.  Genome-wide maps of polyadenylation reveal dynamic mRNA 3'-end formation in mammalian cell lineages. , 2013, RNA.

[205]  H. Juan,et al.  Differential MicroRNA Regulation Correlates with Alternative Polyadenylation Pattern between Breast Cancer and Normal Cells , 2013, PloS one.

[206]  A. Turner,et al.  Endothelin-Converting Enzyme-1 (ECE-1) Is Post-Transcriptionally Regulated by Alternative Polyadenylation , 2014, PloS one.

[207]  L. McDaniel,et al.  The gene CSTF2T, encoding the human variant CstF-64 polyadenylation protein tauCstF-64, lacks introns and may be associated with male sterility. , 2002, Genomics.

[208]  A. Furger,et al.  Integrating mRNA Processing with Transcription , 2002, Cell.

[209]  Soyoun Kim,et al.  Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA* , 2003, Journal of Biological Chemistry.

[210]  W. Keller,et al.  Position-dependent inhibition of the cleavage step of pre-mRNA 3'-end processing by U1 snRNP. , 2000, RNA.

[211]  Zhenbo Hou,et al.  Profiling of alternative polyadenylation sites in luminal B breast cancer using the SAPAS method , 2014, International journal of molecular medicine.

[212]  Tiffany Y. Hsu,et al.  Genetics and Regulatory Impact of Alternative Polyadenylation in Human B-Lymphoblastoid Cells , 2012, PLoS genetics.

[213]  Bin Tian,et al.  Alternative polyadenylation of cyclooxygenase-2 , 2005, Nucleic acids research.

[214]  N. Proudfoot,et al.  Recruitment of a Basal Polyadenylation Factor by the Upstream Sequence Element of the Human Lamin B2 Polyadenylation Signal , 2000, Molecular and Cellular Biology.

[215]  Q. Li,et al.  Calmodulin Interacts with and Regulates the RNA-Binding Activity of an Arabidopsis Polyadenylation Factor Subunit1[OA] , 2006, Plant Physiology.

[216]  Guoli Ji,et al.  Genome-Wide Control of Polyadenylation Site Choice by CPSF30 in Arabidopsis[C][W][OA] , 2012, Plant Cell.

[217]  F. Rigo,et al.  The RNA tether from the poly(A) signal to the polymerase mediates coupling of transcription to cleavage and polyadenylation. , 2005, Molecular cell.

[218]  C. Johansson,et al.  Regulation of human papillomavirus gene expression by splicing and polyadenylation , 2013, Nature Reviews Microbiology.

[219]  A. Williamson,et al.  THOC5 controls 3′end-processing of immediate early genes via interaction with polyadenylation specific factor 100 (CPSF100) , 2014, Nucleic acids research.

[220]  A. Shyu,et al.  RNA stabilization by the AU‐rich element binding protein, HuR, an ELAV protein , 1998, The EMBO journal.

[221]  Noah Spies,et al.  Biased chromatin signatures around polyadenylation sites and exons. , 2009, Molecular cell.

[222]  Nicholas T. Ingolia,et al.  Mammalian microRNAs predominantly act to decrease target mRNA levels , 2010, Nature.

[223]  H. Okano,et al.  Involvement of Hu and Heterogeneous Nuclear Ribonucleoprotein K in Neuronal Differentiation through p21 mRNA Post-transcriptional Regulation* , 2005, Journal of Biological Chemistry.

[224]  E. Lai,et al.  Widespread and extensive lengthening of 3′ UTRs in the mammalian brain , 2013, Genome research.

[225]  Jennifer L. Bachorik,et al.  Gemin5-snRNA interaction reveals an RNA binding function for WD repeat domains , 2009, Nature Structural &Molecular Biology.

[226]  Rakesh S. Laishram.  Poly(A) polymerase (PAP) diversity in gene expression – Star-PAP vs canonical PAP , 2014, FEBS letters.

[227]  B. Tian,et al.  Reprogramming of 3′ Untranslated Regions of mRNAs by Alternative Polyadenylation in Generation of Pluripotent Stem Cells from Different Cell Types , 2009, PloS one.

[228]  Wei Li,et al.  Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types , 2014, Nature Communications.

[229]  R. Elkon,et al.  The Poly(A)-Binding Protein Nuclear 1 Suppresses Alternative Cleavage and Polyadenylation Sites , 2012, Cell.

[230]  R. Zinkowski,et al.  A novel tau transcript in cultured human neuroblastoma cells expressing nuclear tau , 1993, The Journal of cell biology.

[231]  C. Mayr,et al.  Widespread Shortening of 3′UTRs by Alternative Cleavage and Polyadenylation Activates Oncogenes in Cancer Cells , 2009, Cell.

[232]  J. Manley,et al.  A multisubunit factor, CstF, is required for polyadenylation of mammalian pre-mRNAs. , 1990, Genes & development.

[233]  K. Murthy,et al.  The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3'-end formation. , 1995, Genes & development.

[234]  J. Tam,et al.  A novel function for the U2AF 65 splicing factor in promoting pre‐mRNA 3′‐end processing , 2002, EMBO reports.

[235]  Julie L. Yang,et al.  Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression , 2013, Genes & development.

[236]  V. Beneš,et al.  Diverse roles of hnRNP L in mammalian mRNA processing: a combined microarray and RNAi analysis. , 2007, RNA.

[237]  A. Krogh,et al.  Alternative Polyadenylation of Tumor Suppressor Genes in Small Intestinal Neuroendocrine Tumors , 2014, Front. Endocrinol..

[238]  E. Evguenieva-Hackenberg,et al.  New aspects of RNA processing in prokaryotes. , 2011, Current opinion in microbiology.

[239]  M. Wollerton,et al.  Polypyrimidine Tract Binding Protein Modulates Efficiency of Polyadenylation , 2004, Molecular and Cellular Biology.

[240]  C. Burge,et al.  3′ UTR-isoform choice has limited influence on the stability and translational efficiency of most mRNAs in mouse fibroblasts , 2013, Genome research.

[241]  Peter J. Shepard,et al.  Complex and dynamic landscape of RNA polyadenylation revealed by PAS-Seq. , 2011, RNA.

[242]  J. McLauchlan,et al.  The consensus sequence YGTGTTYY located downstream from the AATAAA signal is required for efficient formation of mRNA 3' termini. , 1985, Nucleic acids research.

[243]  Bin Tian,et al.  A functional human Poly(A) site requires only a potent DSE and an A-rich upstream sequence , 2010, The EMBO journal.

[244]  H. Handa,et al.  Knock-down of 25 kDa subunit of cleavage factor Im in Hela cells alters alternative polyadenylation within 3′-UTRs , 2006, Nucleic acids research.

[245]  A. Riccio,et al.  An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons , 2010, Nature Neuroscience.

[246]  Patrice M. Milos,et al.  An in-depth map of polyadenylation sites in cancer , 2012, Nucleic acids research.

[247]  Vicent Pelechano,et al.  An efficient method for genome-wide polyadenylation site mapping and RNA quantification , 2013, Nucleic acids research.

[248]  Diana Blank,et al.  Yhh1p/Cft1p directly links poly(A) site recognition and RNA polymerase II transcription termination , 2002, The EMBO journal.

[249]  S. Rose,et al.  In vitro polyadenylation is stimulated by the presence of an upstream intron. , 1990, Genes & development.

[250]  T. Elton,et al.  Human phosducin-like protein (hPhLP) messenger RNA stability is regulated by cis-acting instability elements present in the 3'-untranslated region. , 1999, Biochimica et biophysica acta.

[251]  Pedro G. Ferreira,et al.  CPEB1 coordinates alternative 3′-UTR formation with translational regulation , 2013, Nature.

[252]  M. Levine,et al.  ELAV links paused Pol II to alternative polyadenylation in the Drosophila nervous system. , 2015, Molecular cell.

[253]  Tyson A. Clark,et al.  HITS-CLIP yields genome-wide insights into brain alternative RNA processing , 2008, Nature.

[254]  Paolo Provero,et al.  Shortening of 3′UTRs Correlates with Poor Prognosis in Breast and Lung Cancer , 2012, PloS one.

[255]  J. Graber,et al.  Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes. , 2009, Cancer research.

[256]  A. Furger,et al.  Subcellular RNA profiling links splicing and nuclear DICER1 to alternative cleavage and polyadenylation , 2016, Genome research.

[257]  V. Kim,et al.  TAIL-seq: genome-wide determination of poly(A) tail length and 3' end modifications. , 2014, Molecular cell.

[258]  C. Milcarek,et al.  Elevated Levels of the 64-kDa Cleavage Stimulatory Factor (CstF-64) in Lipopolysaccharide-stimulated Macrophages Influence Gene Expression and Induce Alternative Poly(A) Site Selection* , 2005, Journal of Biological Chemistry.

[259]  A. Wood,et al.  Epigenetic control of alternative mRNA processing at the imprinted Herc3/Nap1l5 locus , 2012, Nucleic acids research.

[260]  C. MacDonald,et al.  Polyadenylation site-specific differences in the activity of the neuronal βCstF-64 protein in PC-12 cells. , 2013, Gene.

[261]  J. Manley,et al.  Complex Protein Interactions within the Human Polyadenylation Machinery Identify a Novel Component , 2000, Molecular and Cellular Biology.

[262]  J. Nevins,et al.  Poly(A) site cleavage in a HeLa nuclear extract is dependent on downstream sequences , 1985, Cell.

[263]  R. Elkon,et al.  E2F mediates enhanced alternative polyadenylation in proliferation , 2012, Genome Biology.

[264]  N. Goshima,et al.  Alternative 3′‐end processing of long noncoding RNA initiates construction of nuclear paraspeckles , 2012, The EMBO journal.

[265]  Hang Wang,et al.  Pre-Messenger RNA Cleavage Factor I (CFIm): Potential Role in Alternative Polyadenylation During Spermatogenesis1 , 2008, Biology of reproduction.

[266]  Christine Mayr,et al.  Alternative 3'UTRs act as scaffolds to regulate membrane protein localization , 2015, Nature.

[267]  N. Proudfoot,et al.  Human Pcf11 enhances degradation of RNA polymerase II-associated nascent RNA and transcriptional termination , 2007, Nucleic acids research.

[268]  K. Venkataraman,et al.  Analysis of a noncanonical poly(A) site reveals a tripartite mechanism for vertebrate poly(A) site recognition. , 2005, Genes & development.

[269]  Lucie N. Hutchins,et al.  Systematic variation in mRNA 3′-processing signals during mouse spermatogenesis , 2006, Nucleic acids research.

[270]  L. Tong,et al.  Protein factors in pre-mRNA 3′-end processing , 2008, Cellular and Molecular Life Sciences.

[271]  C. MacDonald,et al.  Tissue‐specific mechanisms of alternative polyadenylation: testis, brain, and beyond , 2010, Wiley interdisciplinary reviews. RNA.

[272]  Andrew H. Beck,et al.  3′-End Sequencing for Expression Quantification (3SEQ) from Archival Tumor Samples , 2010, PloS one.

[273]  Tyra Hall-Pogar,et al.  Specific trans-acting proteins interact with auxiliary RNA polyadenylation elements in the COX-2 3'-UTR. , 2007, RNA.

[274]  N. Proudfoot,et al.  Poly(A) site selection in the HIV-1 provirus: inhibition of promoter-proximal polyadenylation by the downstream major splice donor site. , 1995, Genes & development.

[275]  B. Glaunsinger,et al.  Aberrant Herpesvirus-Induced Polyadenylation Correlates With Cellular Messenger RNA Destruction , 2009, PLoS biology.

[276]  S. Goodbourn,et al.  Alpha-thalassaemia caused by a polyadenylation signal mutation. , 1983, Nature.

[277]  Auinash Kalsotra,et al.  Systematic Profiling of Poly(A)+ Transcripts Modulated by Core 3’ End Processing and Splicing Factors Reveals Regulatory Rules of Alternative Cleavage and Polyadenylation , 2015, PLoS genetics.

[278]  N. Woo,et al.  Distinct Role of Long 3′ UTR BDNF mRNA in Spine Morphology and Synaptic Plasticity in Hippocampal Neurons , 2008, Cell.