可变多聚腺苷酸化与肿瘤
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摘要
可变多聚腺苷酸化(alternative polyadenylation, APA)是真核细胞mRNA成熟过程中针对前体mRNA 3′端的一种加工修饰方式,是重要的转录后调控机制。APA通过调控3′非翻译区(3′UTR)长度而影响mRNA稳定性、翻译效率和定位。内含子多聚腺苷酸化(intronic polyadenylation, IPA)通过形成丢失重要结构域的截短型蛋白实现对靶基因的调控,参与形成肿瘤新抗原。APA具有肿瘤特异性,有可能用于肿瘤分子分型和靶向治疗。现对APA的形成过程和分类、高通量发现APA的测序和分析技术进展,以及APA对肿瘤发生发展的影响进行综述。
Alternative polyadenylation(APA) is a processing and modification mechanism occurring at 3′ ends of pre-mRNA during eukaryotic mRNA maturation, which is an important regulatory mechanism of gene posttranscription. APA can affect mRNA stability, translation efficiency, and location of mRNA by regulating the length of the 3′ untranslated region(3′ UTR). Intronic polyadenylation(IPA) regulates gene functions and causes tumor neoantigens formation by forming truncated proteins that lose important domains. APA has tumor specificity and may be used for cancer molecular classifications and targeted therapy. This review summarized the formation mechanism and categories of APA, the development of high-throughput sequencing and bioinformatics analysis algorithm applied for APA analysis, and the impact on tumorigenesis APA resulted in.
Alternative polyadenylation(APA) is a processing and modification mechanism occurring at 3′ ends of pre-mRNA during eukaryotic mRNA maturation, which is an important regulatory mechanism of gene posttranscription. APA can affect mRNA stability, translation efficiency, and location of mRNA by regulating the length of the 3′ untranslated region(3′ UTR). Intronic polyadenylation(IPA) regulates gene functions and causes tumor neoantigens formation by forming truncated proteins that lose important domains. APA has tumor specificity and may be used for cancer molecular classifications and targeted therapy. This review summarized the formation mechanism and categories of APA, the development of high-throughput sequencing and bioinformatics analysis algorithm applied for APA analysis, and the impact on tumorigenesis APA resulted in.
引文
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[18]Masamha CP, Xia Z, Yang J, et al. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression.Nature, 2014, 510:412-6
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[20]Sandberg R, Neilson JR, Sarma A, et al. Proliferating cells express mRNAs with shortened 3′untranslated regions and fewer microRNA target sites. Science, 2008, 320:1643-7
[21]Singh I, Lee SH, Sperling AS, et al. Widespread intronic polyadenylation diversifies immune cell transcriptomes.Nat Commun, 2018, 9:1716
[22]Xiang Y, Ye Y, Lou Y, et al. Comprehensive characterization of alternative polyadenylation in human cancer. J Natl Cancer Inst, 2018, 110:379-89
[23]Gillen AE, Brechbuhl HM, Yamamoto TM, et al. Alternative polyadenylation of PRELID1 regulates mitochondrial ROS signaling and cancer outcomes. Mol Cancer Res,2017, 15:1741-51
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[27]Akman BH, Can T, Erson-Bensan AE. Estrogen-induced upregulation and 3′-UTR shortening of CDC6. Nucleic Acids Res, 2012, 40:10679-88
[28]Devany E, Park JY, Murphy MR, et al. Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA. Cell Discov,2016, 2:16013
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[30]Jia X, Yuan S, Wang Y, et al. The role of alternative polyadenylation in the antiviral innate immune response. Nat Commun, 2017, 8:14605
[31]Gruber AR, Martin G, Müller P, et al. Global 3′UTR shortening has a limited effect on protein abundance in proliferating T cells. Nat Commun, 2014, 5:5465
[32]Lee S, Singh I, Tisdale S, et al. Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia. Nature, 2018, 561:127-31
[33]Ni TK, Kuperwasser C. Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer. Elife, 2016, 5:pii:e14730
[34]Taliaferro JM, Vidaki M, Oliveira R, et al. Distal alternative last exons localize mRNAs to neural projections. Mol Cell, 2016, 61:821-33
[35]Berkovits BD, Mayr C. Alternative 3′UTRs act as scaffolds to regulate membrane protein localization. Nature,2015, 522:363-7
[36]Kahles A, Lehmann KV, Toussaint NC, et al. Comprehensive analysis of alternative splicing across tumors from8 705 patients. Cancer Cell, 2018, 34:211-24
[37]Begik O, Oyken M, Cinkilli Alican T, et al. Alternative polyadenylation patterns for novel gene discovery and classification in cancer. Neoplasia, 2017, 19:574-82
[38]Liu VWS, Yau WL, Tam CW, et al. Melatonin inhibits androgen receptor splice variant-7(AR-V7)-induced nuclearfactor-κB(NF-κB)activationandNF-κB activator-induced AR-V7 expression in prostate cancer cells:potential implications for the use of melatonin in castration-resistant prostate cancer(CRPC)therapy. Int J Mol Sci, 2017, 18:1130
[39]Van Etten JL, Nyquist M, Li Y, et al. Targeting a single alternative polyadenylation site coordinately blocks expression of androgen receptor mRNA splice variants in prostate cancer. Cancer Res, 2017, 77:5228-35
[2]Proudfoot NJ. Ending the message:poly(A)signals then and now. Genes Dev, 2011, 25:1770-82
[3]Shepard PJ, Choi EA, Lu J, et al. Complex and dynamic landscape of RNA polyadenylation revealed by PAS-Seq.RNA, 2011, 17:761-72
[4]Hoque M, Ji Z, Zheng D, et al. Analysis of alternative cleavage and polyadenylation by 3′region extraction and deep sequencing. Nat Methods, 2013, 10:133-9
[5]Xia Z, Donehower LA, Cooper TA, et al. Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types. Nat Commun,2014, 5:5274
[6]Tian B, Manley JL. Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol, 2017, 18:18-30
[7]David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer:pathways and programs unhinged.Genes Dev, 2010, 24:2343-64
[8]Danckwardt S, Hentze MW, Kulozik AE. 3′end mRNA processing:molecular mechanisms and implications for health and disease. EMBO J, 2008, 27:482-98
[9]Millevoi S, Vagner S. Molecular mechanisms of eukaryotic pre-mRNA3′end processing regulation. Nucleic Acids Res, 2010, 38:2757-74
[10]Zhu Y, WangX,ForouzmandE,etal.Molecular mechanisms for CFIm-mediated regulation of mRNA alternative polyadenylation. Mol Cell, 2018, 69:62-74
[11]Yang W, Hsu PL, Yang F, et al. Reconstitution of the CstF complex unveils a regulatory role for CstF-50 in recognition of 3′-end processing signals. Nucleic Acids Res, 2018,46:493-503
[12]Clerici M, Faini M, Aebersold R, et al. Structural insights into the assembly and polyA signal recognition mechanism of the human CPSF complex. Elife, 2017, 6:pii:e33111
[13]Sullivan KD, Steiniger M, Marzluff WF. A core complex of CPSF73, CPSF100, and Symplekin may form two different cleavage factors for processing of poly(A)and histone mRNAs. Mol Cell, 2009, 34:322-32
[14]Sun Y, Zhang Y, Hamilton K, et al. Molecular basis for the recognition of the human AAUAAA polyadenylation signal. Proc Natl Acad Sci USA, 2018, 115:E1419-28
[15]Clerici M, Faini M, Muckenfuss LM, et al. Structural basis of AAUAAA polyadenylation signal recognition by the human CPSF complex. Nat Struct Mol Biol, 2018, 25:135-8
[16]Grozdanov PN, Masoumzadeh E, Latham MP, et al. The structural basis of CstF-77 modulation of cleavage and polyadenylation through stimulation of CstF-64 activity.Nucleic Acids Res, 2018, 46:12022-39
[17]Hockert JA, Yeh HJ, MacDonald CC. The hinge domain of the cleavage stimulation factor protein CstF-64 is essential for CstF-77 interaction, nuclear localization, and polyadenylation. J Biol Chem, 2010, 285:695-704
[18]Masamha CP, Xia Z, Yang J, et al. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression.Nature, 2014, 510:412-6
[19]Sch?fer P, Tüting C, Sch?nemann L et al. Reconstitution of mammalian cleavage factor II involved in 3′processing of mRNA precursors. RNA, 2018, 24:1721-37
[20]Sandberg R, Neilson JR, Sarma A, et al. Proliferating cells express mRNAs with shortened 3′untranslated regions and fewer microRNA target sites. Science, 2008, 320:1643-7
[21]Singh I, Lee SH, Sperling AS, et al. Widespread intronic polyadenylation diversifies immune cell transcriptomes.Nat Commun, 2018, 9:1716
[22]Xiang Y, Ye Y, Lou Y, et al. Comprehensive characterization of alternative polyadenylation in human cancer. J Natl Cancer Inst, 2018, 110:379-89
[23]Gillen AE, Brechbuhl HM, Yamamoto TM, et al. Alternative polyadenylation of PRELID1 regulates mitochondrial ROS signaling and cancer outcomes. Mol Cancer Res,2017, 15:1741-51
[24]Mayr C, Bartel DP. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell, 2009, 138:673-84
[25]Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell, 2003, 3:185-97
[26]Passacantilli I, Panzeri V, Bielli P, et al. Alternative polyadenylation of ZEB1 promotes its translation during genotoxic stress in pancreatic cancer cells. Cell Death Dis,2017, 8:e3168
[27]Akman BH, Can T, Erson-Bensan AE. Estrogen-induced upregulation and 3′-UTR shortening of CDC6. Nucleic Acids Res, 2012, 40:10679-88
[28]Devany E, Park JY, Murphy MR, et al. Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA. Cell Discov,2016, 2:16013
[29]Zheng D, Wang R, Q D, et al. Cellular stress alters 3′UTR landscape through alternative polyadenylation and isoform-specific degradation. Nat Commun, 2018, 9:2268
[30]Jia X, Yuan S, Wang Y, et al. The role of alternative polyadenylation in the antiviral innate immune response. Nat Commun, 2017, 8:14605
[31]Gruber AR, Martin G, Müller P, et al. Global 3′UTR shortening has a limited effect on protein abundance in proliferating T cells. Nat Commun, 2014, 5:5465
[32]Lee S, Singh I, Tisdale S, et al. Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia. Nature, 2018, 561:127-31
[33]Ni TK, Kuperwasser C. Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer. Elife, 2016, 5:pii:e14730
[34]Taliaferro JM, Vidaki M, Oliveira R, et al. Distal alternative last exons localize mRNAs to neural projections. Mol Cell, 2016, 61:821-33
[35]Berkovits BD, Mayr C. Alternative 3′UTRs act as scaffolds to regulate membrane protein localization. Nature,2015, 522:363-7
[36]Kahles A, Lehmann KV, Toussaint NC, et al. Comprehensive analysis of alternative splicing across tumors from8 705 patients. Cancer Cell, 2018, 34:211-24
[37]Begik O, Oyken M, Cinkilli Alican T, et al. Alternative polyadenylation patterns for novel gene discovery and classification in cancer. Neoplasia, 2017, 19:574-82
[38]Liu VWS, Yau WL, Tam CW, et al. Melatonin inhibits androgen receptor splice variant-7(AR-V7)-induced nuclearfactor-κB(NF-κB)activationandNF-κB activator-induced AR-V7 expression in prostate cancer cells:potential implications for the use of melatonin in castration-resistant prostate cancer(CRPC)therapy. Int J Mol Sci, 2017, 18:1130
[39]Van Etten JL, Nyquist M, Li Y, et al. Targeting a single alternative polyadenylation site coordinately blocks expression of androgen receptor mRNA splice variants in prostate cancer. Cancer Res, 2017, 77:5228-35