RNA Processing.BCH6415.Spr2006.PartII print

RNA Processing.BCH6415.Spr2006.PartII print - RNA...

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RNA PROCESSING BCH 6415 Dr. Yang Spring 2006 Part I
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Transcription termination, mRNA Stability, and Turnover 1) mRNA Decay 3) Nonsense-mediated decay
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Messenger RNA decay pathways in eukaryotic cells. The left panel depicts deadenylation-dependent mRNA decay. Deadenylases remove the poly(A) tail which then allows decapping and 5'-3' degradation. Additionally following deadenylation, the exosome can execute 3'-5' decay of the mRNA body. In mammalian cells, 3'-5' decay can occur without prior decapping. In the nonstop decay pathway, removal of the poly(A) tail and 3'-5' degradation of the mRNA body requires only the exosome and associated factors; the major deadenylases are not involved. The right panel depicts deadenylation-independent decay pathways. Following endonucleolytic cleavage of a mRNA, the two products can undergo both 5'-3' and 3'-5' degradation to complete destruction of the mRNA. In the NMD pathway of S. cerevisiae, decapping ensues without prior deadenylation, followed by 5'-3' degradation. The NMD pathway in mammalian cells is still unclear. Brewer, G. Aging Res. Rev. 1:607; 2002
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Current model of mammalian mRNA degradation pathways. Cytoplasmic mRNA degradation starts with deadenylation, a 3' 5' exonucleolytic shortening of the poly(A) tail mediated by the consecutive activity of two different deadenylases. During the first phase of deadenylation, PAN2–PAN3 shortens the poly(A) tails to 110 A nucleotides. PAN2–PAN3 is then replaced by CCR4–CAF1 for the second phase of deadenylation. During the CCR4–CAF1–mediated phase of deadenylation, the decapping enzyme (consisting of Dcp2, Dcp1 and additional factors) can remove the 7-methylguanosine cap from the 5' end of the mRNA, which renders the mRNA susceptible to rapid 5' 3' exonucleolytic degradation by Xrn1. Alternatively or in parallel, CCR4–CAF1 is replaced by the exosome when only a few As are left at the 3' end. The exosome then degrades the mRNA body from the 3' end. Mammalian NMD also uses this PAN2-PAN3/CCR4-CAF1 deadenylation pathway. Fr. Muhlmann 2005 Switch from PAN2-PAN3 deadenylation to CCR4-CAF1 adenylation may be mediated by PABP; PAN2-PAN3 stimulated by PABP
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Wilusz et al. Nat. Rev. Molec Cell Biol . 2:237; 2001 Deadenylation-dependent mRNA decay (in yeast) Endoribonucleolytic decay (Cap removal occurs when poly(A) tail ~10 nts.) Close physical & functioanal interaction bwtn 5’ cap and 3’ poly(A) tail complex, as well as translation initiation and mRNA decay Poly(A)-binding protein (Pab1/PAB1) bound to poly(A) tail inhibits decapping interaction btwn 5’ and 3’ ends of mRNA (circularization?) 2 potential deadenylases: poly(A)-binding protein (Pab)1-dependent Poly(A) nuclease (Pan2/pan3); Ccr4/Caf1 In mammals, deadenylase may be PARN (poly(A) ribonuclease) Cap complex bound by eIF4F [=eIF4E + eIF4G (binds PAB1) + eiF-4A] Deadenylation inhibits translation initiation interaction btwn 3’ poly(A) tail and 5’ cap complex
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RNA Processing.BCH6415.Spr2006.PartII print - RNA...

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