| Structural highlights
Function
[PAN3_YEAST] Regulatory subunit of the poly(A)-nuclease (PAN) deadenylation complex, one of two cytoplasmic mRNA deadenylases involved in mRNA turnover. PAN specifically shortens poly(A) tails of RNA when the poly(A) stretch is bound by poly(A)-binding protein PAB1, which is followed by rapid degradation of the shortened mRNA tails by the CCR4-NOT complex. Deadenylated mRNAs are then degraded by two alternative mechanisms, namely exosome-mediated 3'-5' exonucleolytic degradation, or deadenlyation-dependent mRNA decaping by DCP1-DCP2 and subsequent 5'-3' exonucleolytic degradation by XRN1. May also be involved in post-transcriptional maturation of mRNA poly(A) tails, trimming the tails from their synthesized length to the slightly shorter, apparently messenger-specific length found on newly exported mRNAs.. PAN3 acts as a positive regulator for PAN activity, recruiting the catalytic subunit PAN2 to mRNA via its interaction with PAB1. PAN cooperates with protein kinase DUN1 in the regulation of RAD5 mRNA levels and cell survival in response to replicational stress.[1] [2] [3] [4] [5] [PAN2_YEAST] Catalytic subunit of the poly(A)-nuclease (PAN) deadenylation complex, one of two cytoplasmic mRNA deadenylases involved in mRNA turnover. PAN specifically shortens poly(A) tails of RNA when the poly(A) stretch is bound by poly(A)-binding protein PAB1, which is followed by rapid degradation of the shortened mRNA tails by the CCR4-NOT complex. Deadenylated mRNAs are then degraded by two alternative mechanisms, namely exosome-mediated 3'-5' exonucleolytic degradation, or deadenlyation-dependent mRNA decaping by DCP1-DCP2 and subsequent 5'-3' exonucleolytic degradation by XRN1. May also be involved in post-transcriptional maturation of mRNA poly(A) tails, trimming the tails from their synthesized length to the slightly shorter, apparently messenger-specific length found on newly exported mRNAs. PAN cooperates with protein kinase DUN1 in the regulation of RAD5 mRNA levels and cell survival in response to replicational stress.[6] [7] [8] [9] [10] [11] [12] [13] [PABP_YEAST] Binds the poly(A) tail of mRNA. Appears to be an important mediator of the multiple roles of the poly(A) tail in mRNA biogenesis, stability and translation. In the nucleus, interacts with the nuclear cleavage factor IA (CFIA), which is required for both mRNA cleavage and polyadenylation. Is also required for efficient mRNA export to the cytoplasm. Acts in concert with a poly(A)-specific nuclease (PAN) to affect poly(A) tail shortening, which may occur concomitantly with either nucleocytoplasmic mRNA transport or translational initiation. Regulates PAN activity via interaction with the stimulator PAN3 or the inhibitor PBP1. In the cytoplasm, affects both translation and mRNA decay. Stimulates translation by interaction with translation initiation factor eIF4G, a subunit of the cap-binding complex eIF4F, bringing the 5'- and 3'-ends of the mRNA in proximity. The formation of this circular mRNP structure appears to be critical for the synergistic effects of the cap and the poly(A) tail in facilitating translation initiation, recycling of ribosomes, and mRNA stability. Also regulates translation termination by recruiting eukaryotic release factor 3 (eRF3). Interaction with eRF3 is also required for regulation of normal mRNA decay through translation termination-coupled poly(A) shortening, probably mediated by PAN. Loss of PAB1 from the mRNP after deadenylation triggers mRNA degradation. Inhibits the major cytoplasmic mRNA deadenylase CCR4-NOT complex. Is also associated peripherally with COPI vesicles through its interaction with ARF1, and this is required for correct localization of the asymmetrically distributed ASH1 mRNA.[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]
Publication Abstract from PubMed
The stability of eukaryotic mRNAs is dependent on a ribonucleoprotein (RNP) complex of poly(A)-binding proteins (PABPC1/Pab1) organized on the poly(A) tail. This poly(A) RNP not only protects mRNAs from premature degradation but also stimulates the Pan2-Pan3 deadenylase complex to catalyze the first step of poly(A) tail shortening. We reconstituted this process in vitro using recombinant proteins and show that Pan2-Pan3 associates with and degrades poly(A) RNPs containing two or more Pab1 molecules. The cryo-EM structure of Pan2-Pan3 in complex with a poly(A) RNP composed of 90 adenosines and three Pab1 protomers shows how the oligomerization interfaces of Pab1 are recognized by conserved features of the deadenylase and thread the poly(A) RNA substrate into the nuclease active site. The structure reveals the basis for the periodic repeating architecture at the 3' end of cytoplasmic mRNAs. This illustrates mechanistically how RNA-bound Pab1 oligomers act as rulers for poly(A) tail length over the mRNAs' lifetime.
Molecular Basis for poly(A) RNP Architecture and Recognition by the Pan2-Pan3 Deadenylase.,Schafer IB, Yamashita M, Schuller JM, Schussler S, Reichelt P, Strauss M, Conti E Cell. 2019 May 14. pii: S0092-8674(19)30399-X. doi: 10.1016/j.cell.2019.04.013. PMID:31104843[28]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Brown CE, Tarun SZ Jr, Boeck R, Sachs AB. PAN3 encodes a subunit of the Pab1p-dependent poly(A) nuclease in Saccharomyces cerevisiae. Mol Cell Biol. 1996 Oct;16(10):5744-53. PMID:8816488
- ↑ Lowell JE, Rudner DZ, Sachs AB. 3'-UTR-dependent deadenylation by the yeast poly(A) nuclease. Genes Dev. 1992 Nov;6(11):2088-99. PMID:1358757
- ↑ Brown CE, Sachs AB. Poly(A) tail length control in Saccharomyces cerevisiae occurs by message-specific deadenylation. Mol Cell Biol. 1998 Nov;18(11):6548-59. PMID:9774670
- ↑ Hammet A, Pike BL, Heierhorst J. Posttranscriptional regulation of the RAD5 DNA repair gene by the Dun1 kinase and the Pan2-Pan3 poly(A)-nuclease complex contributes to survival of replication blocks. J Biol Chem. 2002 Jun 21;277(25):22469-74. Epub 2002 Apr 12. PMID:11953437 doi:http://dx.doi.org/10.1074/jbc.M202473200
- ↑ Dheur S, Nykamp KR, Viphakone N, Swanson MS, Minvielle-Sebastia L. Yeast mRNA Poly(A) tail length control can be reconstituted in vitro in the absence of Pab1p-dependent Poly(A) nuclease activity. J Biol Chem. 2005 Jul 1;280(26):24532-8. Epub 2005 May 12. PMID:15894541 doi:http://dx.doi.org/M504720200
- ↑ Boeck R, Tarun S Jr, Rieger M, Deardorff JA, Muller-Auer S, Sachs AB. The yeast Pan2 protein is required for poly(A)-binding protein-stimulated poly(A)-nuclease activity. J Biol Chem. 1996 Jan 5;271(1):432-8. PMID:8550599
- ↑ Lowell JE, Rudner DZ, Sachs AB. 3'-UTR-dependent deadenylation by the yeast poly(A) nuclease. Genes Dev. 1992 Nov;6(11):2088-99. PMID:1358757
- ↑ Brown CE, Tarun SZ Jr, Boeck R, Sachs AB. PAN3 encodes a subunit of the Pab1p-dependent poly(A) nuclease in Saccharomyces cerevisiae. Mol Cell Biol. 1996 Oct;16(10):5744-53. PMID:8816488
- ↑ Brown CE, Sachs AB. Poly(A) tail length control in Saccharomyces cerevisiae occurs by message-specific deadenylation. Mol Cell Biol. 1998 Nov;18(11):6548-59. PMID:9774670
- ↑ Tucker M, Valencia-Sanchez MA, Staples RR, Chen J, Denis CL, Parker R. The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae. Cell. 2001 Feb 9;104(3):377-86. PMID:11239395
- ↑ Hammet A, Pike BL, Heierhorst J. Posttranscriptional regulation of the RAD5 DNA repair gene by the Dun1 kinase and the Pan2-Pan3 poly(A)-nuclease complex contributes to survival of replication blocks. J Biol Chem. 2002 Jun 21;277(25):22469-74. Epub 2002 Apr 12. PMID:11953437 doi:http://dx.doi.org/10.1074/jbc.M202473200
- ↑ Dunn EF, Hammell CM, Hodge CA, Cole CN. Yeast poly(A)-binding protein, Pab1, and PAN, a poly(A) nuclease complex recruited by Pab1, connect mRNA biogenesis to export. Genes Dev. 2005 Jan 1;19(1):90-103. PMID:15630021 doi:http://dx.doi.org/19/1/90
- ↑ Dheur S, Nykamp KR, Viphakone N, Swanson MS, Minvielle-Sebastia L. Yeast mRNA Poly(A) tail length control can be reconstituted in vitro in the absence of Pab1p-dependent Poly(A) nuclease activity. J Biol Chem. 2005 Jul 1;280(26):24532-8. Epub 2005 May 12. PMID:15894541 doi:http://dx.doi.org/M504720200
- ↑ Sachs AB, Davis RW. The poly(A) binding protein is required for poly(A) shortening and 60S ribosomal subunit-dependent translation initiation. Cell. 1989 Sep 8;58(5):857-67. PMID:2673535
- ↑ Bernstein P, Peltz SW, Ross J. The poly(A)-poly(A)-binding protein complex is a major determinant of mRNA stability in vitro. Mol Cell Biol. 1989 Feb;9(2):659-70. PMID:2565532
- ↑ Caponigro G, Parker R. Multiple functions for the poly(A)-binding protein in mRNA decapping and deadenylation in yeast. Genes Dev. 1995 Oct 1;9(19):2421-32. PMID:7557393
- ↑ Amrani N, Minet M, Le Gouar M, Lacroute F, Wyers F. Yeast Pab1 interacts with Rna15 and participates in the control of the poly(A) tail length in vitro. Mol Cell Biol. 1997 Jul;17(7):3694-701. PMID:9199303
- ↑ Minvielle-Sebastia L, Preker PJ, Wiederkehr T, Strahm Y, Keller W. The major yeast poly(A)-binding protein is associated with cleavage factor IA and functions in premessenger RNA 3'-end formation. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7897-902. PMID:9223284
- ↑ Coller JM, Gray NK, Wickens MP. mRNA stabilization by poly(A) binding protein is independent of poly(A) and requires translation. Genes Dev. 1998 Oct 15;12(20):3226-35. PMID:9784497
- ↑ Otero LJ, Ashe MP, Sachs AB. The yeast poly(A)-binding protein Pab1p stimulates in vitro poly(A)-dependent and cap-dependent translation by distinct mechanisms. EMBO J. 1999 Jun 1;18(11):3153-63. PMID:10357826 doi:http://dx.doi.org/10.1093/emboj/18.11.3153
- ↑ Tharun S, Parker R. Targeting an mRNA for decapping: displacement of translation factors and association of the Lsm1p-7p complex on deadenylated yeast mRNAs. Mol Cell. 2001 Nov;8(5):1075-83. PMID:11741542
- ↑ Tucker M, Staples RR, Valencia-Sanchez MA, Muhlrad D, Parker R. Ccr4p is the catalytic subunit of a Ccr4p/Pop2p/Notp mRNA deadenylase complex in Saccharomyces cerevisiae. EMBO J. 2002 Mar 15;21(6):1427-36. PMID:11889048 doi:http://dx.doi.org/10.1093/emboj/21.6.1427
- ↑ Hosoda N, Kobayashi T, Uchida N, Funakoshi Y, Kikuchi Y, Hoshino S, Katada T. Translation termination factor eRF3 mediates mRNA decay through the regulation of deadenylation. J Biol Chem. 2003 Oct 3;278(40):38287-91. Epub 2003 Aug 15. PMID:12923185 doi:http://dx.doi.org/10.1074/jbc.C300300200
- ↑ Trautwein M, Dengjel J, Schirle M, Spang A. Arf1p provides an unexpected link between COPI vesicles and mRNA in Saccharomyces cerevisiae. Mol Biol Cell. 2004 Nov;15(11):5021-37. Epub 2004 Sep 8. PMID:15356266 doi:http://dx.doi.org/10.1091/mbc.E04-05-0411
- ↑ Mangus DA, Evans MC, Agrin NS, Smith M, Gongidi P, Jacobson A. Positive and negative regulation of poly(A) nuclease. Mol Cell Biol. 2004 Jun;24(12):5521-33. PMID:15169912 doi:http://dx.doi.org/10.1128/MCB.24.12.5521-5533.2004
- ↑ Dunn EF, Hammell CM, Hodge CA, Cole CN. Yeast poly(A)-binding protein, Pab1, and PAN, a poly(A) nuclease complex recruited by Pab1, connect mRNA biogenesis to export. Genes Dev. 2005 Jan 1;19(1):90-103. PMID:15630021 doi:http://dx.doi.org/19/1/90
- ↑ Brune C, Munchel SE, Fischer N, Podtelejnikov AV, Weis K. Yeast poly(A)-binding protein Pab1 shuttles between the nucleus and the cytoplasm and functions in mRNA export. RNA. 2005 Apr;11(4):517-31. PMID:15769879 doi:http://dx.doi.org/11/4/517
- ↑ Schafer IB, Yamashita M, Schuller JM, Schussler S, Reichelt P, Strauss M, Conti E. Molecular Basis for poly(A) RNP Architecture and Recognition by the Pan2-Pan3 Deadenylase. Cell. 2019 May 14. pii: S0092-8674(19)30399-X. doi: 10.1016/j.cell.2019.04.013. PMID:31104843 doi:http://dx.doi.org/10.1016/j.cell.2019.04.013
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