6h25

Structural highlights

Disease

[EXOS3_HUMAN] Defects in EXOSC3 are the cause of pontocerebellar hypoplasia type 1B (PCH1B) [MIM:614678]. A severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement.^[1]

Function

[EXOS6_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes.^[2] [MPH6_HUMAN] RNA-binding protein that associates with the RNA exosome complex. Involved in the 3'-processing of the 7S pre-RNA to the mature 5.8S rRNA and may play a role in recruiting the RNA exosome complex to pre-rRNA; this function may include C1D.^[3] [EXOS8_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC8 binds to ARE-containing RNAs.^{[4] [5]} [EXOS3_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC3 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC9 and EXOSC5.^{[6] [7] [8] [9]} [EXOS1_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC1 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC6 and EXOSC8. [EXOS4_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC4 binds to ARE-containing RNAs.^{[10] [11] [12] [13] [14]} [EXOS2_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC2 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC4 and EXOSC7.^[15] [EXOS9_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC9 binds to ARE-containing RNAs.^{[16] [17] [18] [19]} [EXOS5_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes.^{[20] [21]} [RRP44_HUMAN] Putative catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. DIS3 has both 3'-5' exonuclease and endonuclease activities.^{[22] [23]} [EXOS7_HUMAN] Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes.

References

1. ↑ Wan J, Yourshaw M, Mamsa H, Rudnik-Schoneborn S, Menezes MP, Hong JE, Leong DW, Senderek J, Salman MS, Chitayat D, Seeman P, von Moers A, Graul-Neumann L, Kornberg AJ, Castro-Gago M, Sobrido MJ, Sanefuji M, Shieh PB, Salamon N, Kim RC, Vinters HV, Chen Z, Zerres K, Ryan MM, Nelson SF, Jen JC. Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet. 2012 Apr 29;44(6):704-8. doi: 10.1038/ng.2254. PMID:22544365 doi:10.1038/ng.2254
2. ↑ Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, Eccleston J, Zhang T, Myers D, Wasserman CR, Wesemann DR, Januszyk K, Gregory RI, Deng H, Lima CD, Alt FW. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011 Feb 4;144(3):353-63. doi: 10.1016/j.cell.2011.01.001. Epub 2011 Jan, 20. PMID:21255825 doi:10.1016/j.cell.2011.01.001
3. ↑ Schilders G, van Dijk E, Pruijn GJ. C1D and hMtr4p associate with the human exosome subunit PM/Scl-100 and are involved in pre-rRNA processing. Nucleic Acids Res. 2007;35(8):2564-72. Epub 2007 Apr 4. PMID:17412707 doi:http://dx.doi.org/10.1093/nar/gkm082
4. ↑ Anderson JR, Mukherjee D, Muthukumaraswamy K, Moraes KC, Wilusz CJ, Wilusz J. Sequence-specific RNA binding mediated by the RNase PH domain of components of the exosome. RNA. 2006 Oct;12(10):1810-6. Epub 2006 Aug 15. PMID:16912217 doi:10.1261/rna.144606
5. ↑ van Dijk EL, Schilders G, Pruijn GJ. Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways. RNA. 2007 Jul;13(7):1027-35. Epub 2007 Jun 1. PMID:17545563 doi:10.1261/rna.575107
6. ↑ Mukherjee D, Gao M, O'Connor JP, Raijmakers R, Pruijn G, Lutz CS, Wilusz J. The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. EMBO J. 2002 Jan 15;21(1-2):165-74. PMID:11782436 doi:10.1093/emboj/21.1.165
7. ↑ van Dijk EL, Schilders G, Pruijn GJ. Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways. RNA. 2007 Jul;13(7):1027-35. Epub 2007 Jun 1. PMID:17545563 doi:10.1261/rna.575107
8. ↑ Preker P, Nielsen J, Kammler S, Lykke-Andersen S, Christensen MS, Mapendano CK, Schierup MH, Jensen TH. RNA exosome depletion reveals transcription upstream of active human promoters. Science. 2008 Dec 19;322(5909):1851-4. doi: 10.1126/science.1164096. Epub 2008, Dec 4. PMID:19056938 doi:10.1126/science.1164096
9. ↑ Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, Eccleston J, Zhang T, Myers D, Wasserman CR, Wesemann DR, Januszyk K, Gregory RI, Deng H, Lima CD, Alt FW. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011 Feb 4;144(3):353-63. doi: 10.1016/j.cell.2011.01.001. Epub 2011 Jan, 20. PMID:21255825 doi:10.1016/j.cell.2011.01.001
10. ↑ Anderson JR, Mukherjee D, Muthukumaraswamy K, Moraes KC, Wilusz CJ, Wilusz J. Sequence-specific RNA binding mediated by the RNase PH domain of components of the exosome. RNA. 2006 Oct;12(10):1810-6. Epub 2006 Aug 15. PMID:16912217 doi:10.1261/rna.144606
11. ↑ van Dijk EL, Schilders G, Pruijn GJ. Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways. RNA. 2007 Jul;13(7):1027-35. Epub 2007 Jun 1. PMID:17545563 doi:10.1261/rna.575107
12. ↑ Mullen TE, Marzluff WF. Degradation of histone mRNA requires oligouridylation followed by decapping and simultaneous degradation of the mRNA both 5' to 3' and 3' to 5'. Genes Dev. 2008 Jan 1;22(1):50-65. doi: 10.1101/gad.1622708. PMID:18172165 doi:10.1101/gad.1622708
13. ↑ Slomovic S, Fremder E, Staals RH, Pruijn GJ, Schuster G. Addition of poly(A) and poly(A)-rich tails during RNA degradation in the cytoplasm of human cells. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7407-12. doi:, 10.1073/pnas.0910621107. Epub 2010 Apr 5. PMID:20368444 doi:10.1073/pnas.0910621107
14. ↑ Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, Eccleston J, Zhang T, Myers D, Wasserman CR, Wesemann DR, Januszyk K, Gregory RI, Deng H, Lima CD, Alt FW. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011 Feb 4;144(3):353-63. doi: 10.1016/j.cell.2011.01.001. Epub 2011 Jan, 20. PMID:21255825 doi:10.1016/j.cell.2011.01.001
15. ↑ van Dijk EL, Schilders G, Pruijn GJ. Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways. RNA. 2007 Jul;13(7):1027-35. Epub 2007 Jun 1. PMID:17545563 doi:10.1261/rna.575107
16. ↑ Mukherjee D, Gao M, O'Connor JP, Raijmakers R, Pruijn G, Lutz CS, Wilusz J. The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. EMBO J. 2002 Jan 15;21(1-2):165-74. PMID:11782436 doi:10.1093/emboj/21.1.165
17. ↑ West S, Gromak N, Norbury CJ, Proudfoot NJ. Adenylation and exosome-mediated degradation of cotranscriptionally cleaved pre-messenger RNA in human cells. Mol Cell. 2006 Feb 3;21(3):437-43. PMID:16455498 doi:http://dx.doi.org/10.1016/j.molcel.2005.12.008
18. ↑ Anderson JR, Mukherjee D, Muthukumaraswamy K, Moraes KC, Wilusz CJ, Wilusz J. Sequence-specific RNA binding mediated by the RNase PH domain of components of the exosome. RNA. 2006 Oct;12(10):1810-6. Epub 2006 Aug 15. PMID:16912217 doi:10.1261/rna.144606
19. ↑ van Dijk EL, Schilders G, Pruijn GJ. Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways. RNA. 2007 Jul;13(7):1027-35. Epub 2007 Jun 1. PMID:17545563 doi:10.1261/rna.575107
20. ↑ Mukherjee D, Gao M, O'Connor JP, Raijmakers R, Pruijn G, Lutz CS, Wilusz J. The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. EMBO J. 2002 Jan 15;21(1-2):165-74. PMID:11782436 doi:10.1093/emboj/21.1.165
21. ↑ Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, Eccleston J, Zhang T, Myers D, Wasserman CR, Wesemann DR, Januszyk K, Gregory RI, Deng H, Lima CD, Alt FW. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011 Feb 4;144(3):353-63. doi: 10.1016/j.cell.2011.01.001. Epub 2011 Jan, 20. PMID:21255825 doi:10.1016/j.cell.2011.01.001
22. ↑ Preker P, Nielsen J, Kammler S, Lykke-Andersen S, Christensen MS, Mapendano CK, Schierup MH, Jensen TH. RNA exosome depletion reveals transcription upstream of active human promoters. Science. 2008 Dec 19;322(5909):1851-4. doi: 10.1126/science.1164096. Epub 2008, Dec 4. PMID:19056938 doi:10.1126/science.1164096
23. ↑ Tomecki R, Kristiansen MS, Lykke-Andersen S, Chlebowski A, Larsen KM, Szczesny RJ, Drazkowska K, Pastula A, Andersen JS, Stepien PP, Dziembowski A, Jensen TH. The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L. EMBO J. 2010 Jul 21;29(14):2342-57. doi: 10.1038/emboj.2010.121. Epub 2010 Jun 8. PMID:20531386 doi:http://dx.doi.org/10.1038/emboj.2010.121
24. ↑ Gerlach P, Schuller JM, Bonneau F, Basquin J, Reichelt P, Falk S, Conti E. Distinct and evolutionary conserved structural features of the human nuclear exosome complex. Elife. 2018 Jul 26;7. pii: 38686. doi: 10.7554/eLife.38686. PMID:30047866 doi:http://dx.doi.org/10.7554/eLife.38686