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The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements

The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. EMBO J . 2002 January 15; 21(1-2): 165–174. Devi Mukherjee, Min Gao, J.Patrick O’Connor, Reinout Raijmakers, Ger Pruijn, Carol S. Lutz, and Jeffrey Wilusz. Mike 8/11. Exosome Journal Club.

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The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements

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  1. The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements EMBO J. 2002 January 15; 21(1-2): 165–174. Devi Mukherjee, Min Gao, J.Patrick O’Connor, Reinout Raijmakers, Ger Pruijn, Carol S. Lutz, and Jeffrey Wilusz Mike 8/11 Exosome Journal Club

  2. substrate specificity mechanisms (determining substrate specificity) (exosome is recruited to substrate RNA ) Exosome RNA The enzyme and the control of eukaryotic mRNA turnover Nature Struct. Mol. Biol. 2004, 11, 121-126. 1.ARE(AU-rich elements)-binding proteins TTP, RSAU and KSRP interact with exosome and recruit it to mRNA. 2.Exosome subunit (PM/Scl-75) binds ARE.

  3. The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation. 1.Labile mRNAs that encode cytokine and immediate-early gene products often contain AU-rich sequences within their 3' untranslated region (UTR). 2.UUAUUUAUU is the minimal AU-rich motif that effectively destabilizes mRNA. Mol Cell Biol. 1995 Apr;15(4):2219-30

  4. AU binding proteins recruit the exosome to degrade ARE-containing mRNAs Cell, Vol 107, 451-464, 16 November 2001 1.Mammalian exosome is required for rapid degradation of ARE-containing RNAs . 2. ARE recognition requires certain ARE binding proteins (KSRP,TTP, AUF1 and HuR) that can interact with the exosome and recruit it to unstable RNAs, thereby promoting their rapid degradation.

  5. 3’-5’exonucleolytic degradation is responsible for the decay of RNA substrates following deadenylation in HeLa cytoplasmic extracts. Yeast mRNA turnover intermediates Poly (G) AUG UAA Phosphothioate HeLa Cell deadenylation exosome 3’-5’ exonucleolytic decay is the major, if not exclusive, pathway for turnover of mRNA following deadenylation in HeLa cytoplasmic extracts.

  6. Exosomal proteins are required for 3’-5’ exonucleolytic decay in HeLa cytoplasmic extracts. Immunodepletetion experiments

  7. Exosome activity is regulated by AU-rich elements in mammalian cells.

  8. PM-Scl75 protein interacts with RNAs that contain AU-rich instability elements. ARE-TNF- ARE (34) ARE-GMCSF ARE(51)

  9. PM-Scl75 protein interacts with RNAs that contain AU-rich instability elements.

  10. Summery 1. 3’-5’exonucleolytic degradation is responsible for the decay of RNA substrates following deadenylation in HeLa cytoplasmic extracts.2.Exosomal proteins are required for 3’- 5’exonucleolytic decay in HeLa cytoplasmic extracts.3.Exosome activity is regulated by AU-rich elements in mammalian cells.4.PM-Scl75 protein interacts with RNAs that contain AU-rich instability elements. Model 1.Loading the exosome complex onto mRNA is promoted by AREs in 3’- UTR. 2.Exosome may help promote mRNA deadenylation. 3.mRNA is degraded rapidly by exosome.

  11. m7Gppp AUG UAA A 60 m7Gppp AUG UAA A 70 1. 5’- 3’exonuclease activities exist in HeLa cytoplasmic extracts Capped and polyadenylated RNA substrates are very stable in HeLa cytoplasmic extracts substrate : SV-A60 RNA

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