| Structural highlights
Function
[LT_SV40] Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription. May inactivate the growth-suppressing properties of the E3 ubiquitin ligase CUL7.[1] [2] [3] [4] [5] [6] [7] Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.[8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
DNA replication is a fundamental biological process. The initial step in eukaryotic DNA replication is the assembly of the pre-initiation complex, including the formation of two head-to-head hexameric helicases around the replication origin. How these hexameric helicases interact with their origin dsDNA remains unknown. Here, we report the co-crystal structure of the SV40 Large-T Antigen (LT) hexameric helicase bound to its origin dsDNA. The structure shows that the six subunits form a near-planar ring that interacts with the origin, so that each subunit makes unique contacts with the DNA. The origin dsDNA inside the narrower AAA+ domain channel shows partial melting due to the compression of the two phosphate backbones, forcing Watson-Crick base-pairs within the duplex to flip outward. This structure provides the first snapshot of a hexameric helicase binding to origin dsDNA, and suggests a possible mechanism of origin melting by LT during SV40 replication in eukaryotic cells.
The structure of SV40 large T hexameric helicase in complex with AT-rich origin DNA.,Gai D, Wang D, Li SX, Chen XS Elife. 2016 Dec 6;5. pii: e18129. doi: 10.7554/eLife.18129. PMID:27921994[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Damania B, Alwine JC. TAF-like function of SV40 large T antigen. Genes Dev. 1996 Jun 1;10(11):1369-81. PMID:8647434
- ↑ Damania B, Lieberman P, Alwine JC. Simian virus 40 large T antigen stabilizes the TATA-binding protein-TFIIA complex on the TATA element. Mol Cell Biol. 1998 Jul;18(7):3926-35. PMID:9632777
- ↑ Zalvide J, Stubdal H, DeCaprio JA. The J domain of simian virus 40 large T antigen is required to functionally inactivate RB family proteins. Mol Cell Biol. 1998 Mar;18(3):1408-15. PMID:9488456
- ↑ Skoczylas C, Henglein B, Rundell K. PP2A-dependent transactivation of the cyclin A promoter by SV40 ST is mediated by a cell cycle-regulated E2F site. Virology. 2005 Feb 20;332(2):596-601. PMID:15680424 doi:10.1016/j.virol.2004.12.017
- ↑ Welcker M, Clurman BE. The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4. J Biol Chem. 2005 Mar 4;280(9):7654-8. Epub 2004 Dec 20. PMID:15611062 doi:10.1074/jbc.M413377200
- ↑ Valls E, Blanco-Garcia N, Aquizu N, Piedra D, Estaras C, de la Cruz X, Martinez-Balbas MA. Involvement of chromatin and histone deacetylation in SV40 T antigen transcription regulation. Nucleic Acids Res. 2007;35(6):1958-68. Epub 2007 Mar 6. PMID:17341466 doi:gkl1113
- ↑ Hein J, Boichuk S, Wu J, Cheng Y, Freire R, Jat PS, Roberts TM, Gjoerup OV. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. J Virol. 2009 Jan;83(1):117-27. doi: 10.1128/JVI.01515-08. Epub 2008 Oct 15. PMID:18922873 doi:10.1128/JVI.01515-08
- ↑ Damania B, Alwine JC. TAF-like function of SV40 large T antigen. Genes Dev. 1996 Jun 1;10(11):1369-81. PMID:8647434
- ↑ Damania B, Lieberman P, Alwine JC. Simian virus 40 large T antigen stabilizes the TATA-binding protein-TFIIA complex on the TATA element. Mol Cell Biol. 1998 Jul;18(7):3926-35. PMID:9632777
- ↑ Zalvide J, Stubdal H, DeCaprio JA. The J domain of simian virus 40 large T antigen is required to functionally inactivate RB family proteins. Mol Cell Biol. 1998 Mar;18(3):1408-15. PMID:9488456
- ↑ Skoczylas C, Henglein B, Rundell K. PP2A-dependent transactivation of the cyclin A promoter by SV40 ST is mediated by a cell cycle-regulated E2F site. Virology. 2005 Feb 20;332(2):596-601. PMID:15680424 doi:10.1016/j.virol.2004.12.017
- ↑ Welcker M, Clurman BE. The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4. J Biol Chem. 2005 Mar 4;280(9):7654-8. Epub 2004 Dec 20. PMID:15611062 doi:10.1074/jbc.M413377200
- ↑ Valls E, Blanco-Garcia N, Aquizu N, Piedra D, Estaras C, de la Cruz X, Martinez-Balbas MA. Involvement of chromatin and histone deacetylation in SV40 T antigen transcription regulation. Nucleic Acids Res. 2007;35(6):1958-68. Epub 2007 Mar 6. PMID:17341466 doi:gkl1113
- ↑ Hein J, Boichuk S, Wu J, Cheng Y, Freire R, Jat PS, Roberts TM, Gjoerup OV. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. J Virol. 2009 Jan;83(1):117-27. doi: 10.1128/JVI.01515-08. Epub 2008 Oct 15. PMID:18922873 doi:10.1128/JVI.01515-08
- ↑ Gai D, Wang D, Li SX, Chen XS. The structure of SV40 large T hexameric helicase in complex with AT-rich origin DNA. Elife. 2016 Dec 6;5. pii: e18129. doi: 10.7554/eLife.18129. PMID:27921994 doi:http://dx.doi.org/10.7554/eLife.18129
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