6gmh

Structure of activated transcription complex Pol II-DSIF-PAF-SPT6

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Structural highlights

6gmh is a 10 chain structure with sequence from Homo sapiens and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.1Å
Ligands:	MG, SEP, TPO, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SKI8_HUMAN Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1 (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is required for transcription of Hox and Wnt target genes (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3) (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription (PubMed:16307923, PubMed:19952111, PubMed:20178742). PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors (PubMed:16307923, PubMed:19952111, PubMed:20178742). In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription (PubMed:16307923, PubMed:19952111, PubMed:20178742). Required for mono- and trimethylation on histone H3 'Lys-4' (H3K4me3), dimethylation on histone H3 'Lys-79' (H3K4me3). Required for Hox gene transcription (PubMed:16307923, PubMed:19952111, PubMed:20178742). Also acts as a component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways (PubMed:16024656, PubMed:32006463, PubMed:35120588). The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3'-5' direction and channels mRNA to the cytosolic exosome for degradation (PubMed:32006463, PubMed:35120588). SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling (PubMed:32006463).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Gene regulation involves activation of RNA polymerase II (Pol II) that is paused and bound by the protein complexes DRB sensitivity-inducing factor (DSIF) and negative elongation factor (NELF). Here we show that formation of an activated Pol II elongation complex in vitro requires the kinase function of the positive transcription elongation factor b (P-TEFb) and the elongation factors PAF1 complex (PAF) and SPT6. The cryo-EM structure of an activated elongation complex of Sus scrofa Pol II and Homo sapiens DSIF, PAF and SPT6 was determined at 3.1 A resolution and compared to the structure of the paused elongation complex formed by Pol II, DSIF and NELF. PAF displaces NELF from the Pol II funnel for pause release. P-TEFb phosphorylates the Pol II linker to the C-terminal domain. SPT6 binds to the phosphorylated C-terminal-domain linker and opens the RNA clamp formed by DSIF. These results provide the molecular basis for Pol II pause release and elongation activation.

Structure of activated transcription complex Pol II-DSIF-PAF-SPT6.,Vos SM, Farnung L, Boehning M, Wigge C, Linden A, Urlaub H, Cramer P Nature. 2018 Aug;560(7720):607-612. doi: 10.1038/s41586-018-0440-4. Epub 2018 Aug, 22. PMID:30135578^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhu B, Mandal SS, Pham AD, Zheng Y, Erdjument-Bromage H, Batra SK, Tempst P, Reinberg D. The human PAF complex coordinates transcription with events downstream of RNA synthesis. Genes Dev. 2005 Jul 15;19(14):1668-73. PMID:16024656 doi:https://dx.doi.org/10.1101/gad.1292105
↑ Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D. Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol Cell. 2005 Nov 23;20(4):601-11. PMID:16307923 doi:https://dx.doi.org/S1097-2765(05)01646-1
↑ Chen Y, Yamaguchi Y, Tsugeno Y, Yamamoto J, Yamada T, Nakamura M, Hisatake K, Handa H. DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes Dev. 2009 Dec 1;23(23):2765-77. doi: 10.1101/gad.1834709. PMID:19952111 doi:10.1101/gad.1834709
↑ Kim J, Guermah M, Roeder RG. The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS. Cell. 2010 Feb 19;140(4):491-503. doi: 10.1016/j.cell.2009.12.050. PMID:20178742 doi:10.1016/j.cell.2009.12.050
↑ Zinoviev A, Ayupov RK, Abaeva IS, Hellen CUT, Pestova TV. Extraction of mRNA from Stalled Ribosomes by the Ski Complex. Mol Cell. 2020 Mar 19;77(6):1340-1349.e6. PMID:32006463 doi:10.1016/j.molcel.2020.01.011
↑ Kögel A, Keidel A, Bonneau F, Schäfer IB, Conti E. The human SKI complex regulates channeling of ribosome-bound RNA to the exosome via an intrinsic gatekeeping mechanism. Mol Cell. 2022 Feb 17;82(4):756-769.e8. PMID:35120588 doi:10.1016/j.molcel.2022.01.009
↑ Vos SM, Farnung L, Boehning M, Wigge C, Linden A, Urlaub H, Cramer P. Structure of activated transcription complex Pol II-DSIF-PAF-SPT6. Nature. 2018 Aug;560(7720):607-612. doi: 10.1038/s41586-018-0440-4. Epub 2018 Aug, 22. PMID:30135578 doi:https://dx.doi.org/10.1038/s41586-018-0440-4

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OCA

[1] Zhu B, Mandal SS, Pham AD, Zheng Y, Erdjument-Bromage H, Batra SK, Tempst P, Reinberg D. The human PAF complex coordinates transcription with events downstream of RNA synthesis. Genes Dev. 2005 Jul 15;19(14):1668-73. PMID:16024656 doi:https://dx.doi.org/10.1101/gad.1292105

[2] Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D. Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol Cell. 2005 Nov 23;20(4):601-11. PMID:16307923 doi:https://dx.doi.org/S1097-2765(05)01646-1

[3] Chen Y, Yamaguchi Y, Tsugeno Y, Yamamoto J, Yamada T, Nakamura M, Hisatake K, Handa H. DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes Dev. 2009 Dec 1;23(23):2765-77. doi: 10.1101/gad.1834709. PMID:19952111 doi:10.1101/gad.1834709

[4] Kim J, Guermah M, Roeder RG. The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS. Cell. 2010 Feb 19;140(4):491-503. doi: 10.1016/j.cell.2009.12.050. PMID:20178742 doi:10.1016/j.cell.2009.12.050

[5] Zinoviev A, Ayupov RK, Abaeva IS, Hellen CUT, Pestova TV. Extraction of mRNA from Stalled Ribosomes by the Ski Complex. Mol Cell. 2020 Mar 19;77(6):1340-1349.e6. PMID:32006463 doi:10.1016/j.molcel.2020.01.011

[6] Kögel A, Keidel A, Bonneau F, Schäfer IB, Conti E. The human SKI complex regulates channeling of ribosome-bound RNA to the exosome via an intrinsic gatekeeping mechanism. Mol Cell. 2022 Feb 17;82(4):756-769.e8. PMID:35120588 doi:10.1016/j.molcel.2022.01.009

[7] Vos SM, Farnung L, Boehning M, Wigge C, Linden A, Urlaub H, Cramer P. Structure of activated transcription complex Pol II-DSIF-PAF-SPT6. Nature. 2018 Aug;560(7720):607-612. doi: 10.1038/s41586-018-0440-4. Epub 2018 Aug, 22. PMID:30135578 doi:https://dx.doi.org/10.1038/s41586-018-0440-4

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6gmh

Structure of activated transcription complex Pol II-DSIF-PAF-SPT6

Structural highlights

Function

Publication Abstract from PubMed

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References

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