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Inverted Alu repeats: friends or foes in the human transcriptome

Kim Yoosik|Lee Keonyong|Ku Jayoung|Ku Doyeong
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 1-13|DOI 10.1038/s12276-024-01177-3

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주제분류생화학

초록

Alu elements are highly abundant primate-specific short interspersed nuclear elements that account for ~10% of the human genome. Due to their preferential location in gene-rich regions, especially in introns and 3′ UTRs, Alu elements can exert regulatory effects on the expression of both host and neighboring genes. When two Alu elements with inverse orientations are positioned in close proximity, their transcription results in the generation of distinct double-stranded RNAs (dsRNAs), known as inverted Alu repeats (IRAlus). IRAlus are key immunogenic self-dsRNAs and post-transcriptional cis-regulatory elements that play a role in circular RNA biogenesis, as well as RNA transport and stability. Recently, IRAlus dsRNAs have emerged as regulators of transcription and activators of Z-DNA-binding proteins. The formation and activity of IRAlus can be modulated through RNA editing and interactions with RNA-binding proteins, and misregulation of IRAlus has been implicated in several immune-associated disorders. In this review, we summarize the emerging functions of IRAlus dsRNAs, the regulatory mechanisms governing IRAlus activity, and their relevance in the pathogenesis of human diseases.

Abstract

Alu elements are highly abundant primate-specific short interspersed nuclear elements that account for ~10% of the human genome. Due to their preferential location in gene-rich regions, especially in introns and 3′ UTRs, Alu elements can exert regulatory effects on the expression of both host and neighboring genes. When two Alu elements with inverse orientations are positioned in close proximity, their transcription results in the generation of distinct double-stranded RNAs (dsRNAs), known as inverted Alu repeats (IRAlus). IRAlus are key immunogenic self-dsRNAs and post-transcriptional cis-regulatory elements that play a role in circular RNA biogenesis, as well as RNA transport and stability. Recently, IRAlus dsRNAs have emerged as regulators of transcription and activators of Z-DNA-binding proteins. The formation and activity of IRAlus can be modulated through RNA editing and interactions with RNA-binding proteins, and misregulation of IRAlus has been implicated in several immune-associated disorders. In this review, we summarize the emerging functions of IRAlus dsRNAs, the regulatory mechanisms governing IRAlus activity, and their relevance in the pathogenesis of human diseases.

참고문헌 (117)

  1. Lander, E. S., "Initial sequencing and analysis of the human genome", Nature, 409, pp.860~921 (2001)
  2. Batzer, M. A., "Alu repeats and human genomic diversity", Nat. Rev. Genet, 3, pp.370~379 (2002)
  3. Elder, J. T., "Transcriptional analysis of interspersed repetitive polymerase III transcription units in human DNA", Nucleic Acids Res, 9, pp.1171~1189 (1981)
  4. Dewannieux, M., "LINE-mediated retrotransposition of marked Alu sequences", Nat. Genet, 35, pp.41~48 (2003)
  5. Chen, L. L., "ALUternative regulation for gene expression", Trends Cell Biol, 27, pp.480~490 (2017)
  6. Xie, H., "High-throughput sequence-based epigenomic analysis of Alu repeats in human cerebellum", Nucleic Acids Res, 37, pp.4331~4340 (2009)
  7. Su, M., "Evolution of Alu elements toward enhancers", Cell Rep, 7, pp.376~385 (2014)
  8. Mariner, P. D., "Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock", Mol. Cell, 29, pp.499~509 (2008)
  9. Payer, L. M., "Alu insertion variants alter mRNA splicing", Nucleic Acids Res, 47, pp.421~431 (2019)
  10. Sobczak, K., "Structural determinants of BRCA1 translational regulation", J. Biol. Chem, 277, pp.17349~17358 (2002)
  11. Stuart, J. J., "The 3′ UTR of human MnSOD mRNA hybridizes to a small cytoplasmic RNA and inhibits gene expression", Biochem. Biophys. Res. Commun, 274, pp.641~648 (2000)
  12. Landry, J. R., "Repetitive elements in the 5′untranslated region of a human zinc-finger gene modulate transcription and translation efficiency", Genomics, 76, pp.110~116 (2001)
  13. Chen, L. L., "Alu element-mediated gene silencing", EMBO J, 27, pp.1694~1705 (2008)
  14. Kim, S., "Evidence of aberrant immune response by endogenous double-stranded RNAs : attack from within", BioEssays, 41, pp.1900023~ (2019)
  15. Weber, F., "Double stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses", J. Virol, 80, pp.5059~ (2006)
  16. Hur, S., "Double-stranded RNA sensors and modulators in innate immunity", Annu Rev. Immunol, 37, pp.349~375 (2019)
  17. Kim, Y., "PKR senses nuclear and mitochondrial signals by interacting with endogenous double-stranded RNAs", Mol. Cell, 71, pp.1051~1063 (2018)
  18. Kim, Y., "PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator", Genes Dev, 28, pp.1310~1322 (2014)
  19. Ahmad, S., "Breaching self-tolerance to Alu duplex RNA underlies MDA5mediated inflammation", Cell, 172, pp.797~810 (2018)
  20. Mehdipour, P., "Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency", Nature, 588, pp.169~173 (2020)
  21. Bowling, E. A., "Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer", Cell, 184, pp.384~403 (2021)
  22. Liu, C. X., "Circular RNAs : characterization, cellular roles, and appli cations", Cell, 185, pp.2016~2034 (2022)
  23. Chen, L. L., "Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells : functional role of a nuclear noncoding RNA", Mol. Cell, 35, pp.467~478 (2009)
  24. Aktaş, T., "DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome", Nature, 544, pp.115~119 (2017)
  25. Elbarbary, R. A., "STAU1 binding 3′ UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown", Genes Dev, 27, pp.1495~1510 (2013)
  26. Herzner, A. M., "ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses", J. Exp. Med, 218, pp.e20201833~ (2021)
  27. Chung, H., "Human ADAR1 prevents endogenous RNA from triggering translational shutdown", Cell, 172, pp.811~824 (2018)
  28. Ramaswami, G., "Accurate identification of human Alu and non-Alu RNA editing sites", Nat. Methods, 9, pp.579~581 (2012)
  29. Del Toro Duany, Y., "MDA5-filament, dynamics and disease", Curr. Opin. Virol, 12, pp.20~25 (2015)
  30. Oda, H., "Aicardi-Goutières syndrome is caused by IFIH1 mutations", Am. J. Hum. Genet, 95, pp.121~ (2014)
  31. Kim, B., "Genome-wide mapping of DROSHA cleavage sites on primary MicroRNAs and noncanonical substrates", Mol. Cell, 66, pp.258~269 (2017)
  32. Chitrakar, A., "Introns encode dsRNAs undetected by RIG-I", MDA5, Proc. Natl. Acad. Sci. USA, pp.2021, 118[DOI]
  33. Conti, A., "Identification of RNA polymerase III-transcribed Alu loci by computational screening of RNA-Seq data", Nucleic Acids Res, 43, pp.817~835 (2015)
  34. Moqtaderi, Z., "Genomic binding profiles of functionally distinct RNA polymerase III transcription complexes in human cells", Nat. Struct. Mol. Biol, 17, pp.635~640 (2010)
  35. Chiappinelli, K. B., "Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses", Cell, 162, pp.974~986 (2015)
  36. Roulois, D., "DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts", Cell, 162, pp.961~ (2015)
  37. Wu, Y., "Function of HNRNPC in breast cancer cells by controlling the dsRNA induced interferon response", EMBO J, 37, pp.e99017~ (2018)
  38. Wu, Q., "PRMT inhibition induces a viral mimicry response in triple-negative breast cancer", Nat. Chem. Biol, 18, pp.821~830 (2022)
  39. Guccione, E., "The regulation, functions and clinical relevance of arginine methylation", Nat. Rev. Mol. Cell Biol, 20, pp.642~657 (2019)
  40. Chang, A. Y., "Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response", J. Biol. Chem, 297, pp.101277~ (2021)
  41. Jo, M., "The role of TDP-43 propagation in neurodegenerative diseases : integrating insights from clinical and experimental studies", Exp. Mol. Med, 52, pp.1652~1662 (2020)
  42. Prasad, A., "Molecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis", Front. Mol. Neurosci, 12, pp.436464~ (2019)
  43. Saldi, T. K., "TDP-1, the caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA", EMBO J, 33, pp.2947~2966 (2014)
  44. Dunker, W., "TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response", Cell Rep, 35, pp.108976~ (2021)
  45. Kaneko, H., "DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration", Nature, 471, pp.325~330 (2011)
  46. Tarallo, V., "DICER1 loss and Alu RNA induce age-related macular degen eration via the NLRP3 inflammasome and MyD88", Cell, 149, pp.847~859 (2012)
  47. Kerur, N., "cGAS drives noncanonical-inflammasome activation in age related macular degeneration", Nat. Med, 24, pp.50~61 (2017)
  48. Fukuda, S., "Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity", Sci. Adv, 7, pp.3658~3687 (2021)
  49. Häsler, J., "Alu elements as regulators of gene expression", Nucleic Acids Res, 34, pp.5491~5497 (2006)
  50. Saldi, T., "Alternative RNA structures formed during transcription depend on elongation rate and modify RNA pro cessing", Mol. Cell, 81, pp.1789~1801 (2021)
  51. Borovská, I., "Alu RNA fold links splicing with signal recognition particle proteins", Nucleic Acids Res, 51, pp.8199~8216 (2023)
  52. Nekrutenko, A., "Transposable elements are found in a large number of human protein-coding genes", Trends Genet, 17, pp.619~621 (2001)
  53. Lev-Maor, G., "Intronic Alus influence alternative splicing", PLoS Genet, 4, pp.e1000204~ (2008)
  54. Chen, L. L., "The biogenesis and emerging roles of circular RNAs", Nat. Rev. Mol. Cell Biol, 17, pp.205~211 (2016)
  55. Zhang, Y., "The biogenesis of nascent circular RNAs", Cell Rep, 15, pp.611~624 (2016)
  56. Memczak, S., "Circular RNAs are a large class of animal RNAs with regulatory potency", Nature, 495, pp.333~338 (2013)
  57. Jeck, W. R., "Circular RNAs are abundant, conserved, and associated with ALU repeats", RNA, 19, pp.141~157 (2013)
  58. Zhang, X. O., "Complementary sequence-mediated exon circularization", Cell, 159, pp.134~147 (2014)
  59. Liang, D., "Short intronic repeat sequences facilitate circular RNA production", Genes Dev, 28, pp.2233~2247 (2014)
  60. Ivanov, A., "Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals", Cell Rep, 10, pp.170~177 (2015)
  61. Zhang, X. O., "Diverse alternative back-splicing and alternative splicing landscape of circular RNAs", Genome Res, 26, pp.1277~1287 (2016)
  62. Zhang, P., "Comprehensive identification of alternative back-splicing in human tissue transcriptomes", Nucleic Acids Res, 48, pp.1779~ (2020)
  63. Dong, R., "Increased complexity of circRNA expression during species evolution", RNA Biol, 14, pp.1064~ (2017)
  64. Ottesen, E. W., "A multilayered control of the human survival motor neuron gene expression by Alu elements", Front. Microbiol, 8, pp.2252~ (2017)
  65. Ottesen, E. W., "Human survival motor neuron genes generate a vast repertoire of circular RNAs", Nucleic Acids Res, 47, pp.2884~2905 (2019)
  66. Li, X., "Coordinated circRNA Biogenesis and Function with NF90", NF110 in Viral Infection, 2017, pp.67, 214~227
  67. Pagliarini, V., "Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization", Nucleic Acids Res, 48, pp.633~645 (2020)
  68. Zhang, Z., "The fate of dsRNA in the nucleus : a p54nrb containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs", Cell, 106, pp.465~476 (2001)
  69. Hu, S. B., "Protein arginine methyltransferase CARM1 attenuates the paraspeckle-mediated nuclear retention of mRNAs containing IRAlus", Genes Dev, 29, pp.630~645 (2015)
  70. Torres, M., "Circadian RNA expression elicited by 3′-UTR IRAlu-paraspeckle associated elements", Elife, 5, pp.e14837~ (2016)
  71. Meurs, E. F., "Constitutive expression of human double-stranded RNA-acti vated p68 kinase in murine cells mediates phosphorylation of eukaryotic initiation factor 2 and partial resistance to encephalomyocarditis virus growth", J. Virol, 66, pp.5805~5814 (1992)
  72. Prasanth, K. V., "Regulating gene expression through RNA nuclear retention", Cell, 123, pp.249~263 (2005)
  73. Ku, J., "Alternative polyadenylation determines the functional landscape of inverted Alu repeats", Mol Cell (2024)[DOI]
  74. Kim, Y. K., "Mammalian Staufen1recruits Upf1 to specific mRNA 3′UTRs so as to elicit mRNA decay", Cell, 120, pp.195~208 (2005)
  75. Gong, C., "lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements", Nature, 470, pp.284~290 (2011)
  76. Cho, H., "Staufen1-mediated mRNA decay functions in adipogenesis", Mol. Cell, 46, pp.495~506 (2012)
  77. Gong, C., "SMD and NMD are competitive pathways that contribute to myogenesis : effects on PAX3 and myogenin mRNAs", Genes Dev, 23, pp.54~66 (2009)
  78. Zhao, L., "NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay", Oncogene, 40, pp.4919~4929 (2021)
  79. Liang, L., "Complementary Alu sequences mediate enhancer–promoter selectivity", Nature, pp.1~8 (2023)[DOI]
  80. Kim, T. K., "Architectural and functional commonalities between enhancers and promoters", Cell, 162, pp.948~959 (2015)
  81. Bai, X., "A hypothetical model of trans-acting R-loops-mediated promoter-enhancer interactions by Alu elements", J. Genet. Genom, 48, pp.1007~1019 (2021)
  82. Roundtree, I. A., "Dynamic RNA modifications in gene expression regulation", Cell, 169, pp.1187~1200 (2017)
  83. Boccaletto, P., "MODOMICS: a database of RNA modification pathways. 2021update", Nucleic Acids Res, 50, pp.D231~D235 (2022)
  84. Mannion, N., "New insights into the biological role of mammalian ADARs; the RNA editing proteins", Biomolecules, 5, pp.2338~2362 (2015)
  85. Bahn, J. H., "Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways", Nat. Commun, 6, pp.1~13 (2015)
  86. Bass, B. L., "An unwinding activity that covalently modifies its double-stranded RNA substrate", Cell, 55, pp.1089~1098 (1988)
  87. Liddicoat, B. J., "RNA editing by ADAR1 prevents MDA5 sensing of endo genous dsRNA as nonself", Science, 349, pp.1115~1120 (2015)
  88. Riella, C. V., "ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5activation in a paradoxical biological circuit", Proc. Natl. Acad. Sci. USA, 119, pp.e2210150119~ (2022)
  89. Rice, G. I., "Mutations in ADAR1 cause Aicardi-Goutières syndrome asso ciated with a type I interferon signature", Nat. Genet, 44, pp.1243~1248 (2012)
  90. Li, Q., "RNA editing underlies genetic risk of common inflammatory diseases", Nature, 608, pp.569~577 (2022)
  91. Placido, D., "A left handed RNA double helix bound by the Zα domain of the RNA editing enzyme ADAR1", Structure, 15, pp.395~ (2007)
  92. Tang, Q., "Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses", Immunity, 54, pp.1961~1975 (2021)
  93. de Reuver, R., "ADAR1 interaction with Z-RNA promotes editing of endo genous double-stranded RNA and prevents MDA5-dependent immune activa tion", Cell Rep, 36, pp.109500~ (2021)
  94. Nakahama, T., "Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce Aicardi-Goutières-syndrome-like encepha lopathy", Immunity, 54, pp.1976~1988 (2021)
  95. Herbert, A., "Z-DNA and Z-RNA in human disease", Commun. Biol, 2, pp.1~10 (2019)
  96. de Reuver, R., "ADAR1 prevents autoinflammation by suppressing sponta neous ZBP1 activation", Nature, 607, pp.784~789 (2022)
  97. Obeng, E. A., "Altered RNA processing in cancer pathogenesis and therapy", Cancer Discov, 9, pp.1493~1510 (2019)
  98. Shen, H., "ADARs act as potent regulators of circular transcriptome in cancer", Nat. Commun, 13, pp.1508~ (2022)
  99. Yang, C. C., "ADAR1-mediated 3′ UTR editing and expression control of antiapoptosis genes fine-tunes cellular apoptosis response", Cell Death Dis, 8, pp.e2833~e2833 (2017)
  100. Sakurai, M., "ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay", Nat. Struct. Mol. Biol, 24, pp.534~543 (2017)
  101. Roden, C., "RNA contributions to the form and function of biomolecular condensates", Nat. Rev. Mol. Cell Biol, 22, pp.183~195 (2020)
  102. Paget, M., "Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA", Mol. Cell, 83, pp.1180~1196 (2023)
  103. Corbet, G. A., "dsRNA-induced condensation of antiviral proteins modulates PKR activity", Proc. Natl. Acad. Sci. USA, 119, pp.e2204235119~ (2022)
  104. Gao, Y., "m6A modification prevents formation of endogenous double stranded RNAs and deleterious innate immune responses during hematopoietic development", Immunity, 52, pp.1007~1021 (2020)
  105. Liu, N., "N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions", Nature, 518, pp.560~564 (2015)
  106. Xiang, J. F., "N6-Methyladenosines modulate A-to-I RNA Editing", Mol. Cell, 69, pp.126~135 (2018)
  107. Terajima, H., "N6-methyladenosine promotes induction of ADAR1-mediated A-to-I RNA editing to suppress aberrant antiviral innate immune responses", PLoS Biol, 19, pp.e3001292~ (2021)
  108. Safra, M., "The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution", Nature, 551, pp.251~255 (2017)
  109. Dorrity, T. J., "Long 3′UTRs predispose neurons to inflammation by pro moting immunostimulatory double-stranded RNA formation", Sci. Immunol, 8, pp.eadg2979~ (2023)
  110. Kennedy, E. M., "Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer", Nat. Commun, 13, pp.1~13 (2022)
  111. Garland, K. M., "Nanoparticle delivery of immunostimulatory Alu RNA for cancer immunotherapy", Cancer Res. Commun, 3, pp.1800~ (2023)
  112. Kagan, A. B., "DNA methyltransferase inhibitor exposure–response : chal lenges and opportunities", Clin. Transl. Sci, 16, pp.1309~1322 (2023)
  113. Kang, M., "Double-stranded RNA induction asa potential dynamic bio markerfor DNA-demethylating agents", Mol. Ther. Nucleic Acids, 29, pp.370~383 (2022)
  114. Schaffer, A. A., "The cell line A-to-I RNA editing catalogue", Nucleic Acids Res, 48, pp.5849~5858 (2020)
  115. Cuddleston, W. H., "Cellular and genetic drivers of RNA editing variation in the human brain", Nat. Commun, 13, pp.1~15 (2022)
  116. Shulman, E. D., "Cell-type-specific analysis of alternative poly adenylation using single-cell transcriptomics data", Nucleic Acids Res, 47, pp.10027~10039 (2019)
  117. Xia, Z., "Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types", Nat. Commun, 5, pp.1~13 (2014)

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