Together DSIF and NELF can stall transcription right after initiation by stopping Pol II elongation. P-TEFb can phosphorylate DSIF, NELF, and Pol II to resume transcription. Once phosphorylated NELF falls away while DSIF stimulates elongation.[1]

DSIF (DRB Sensitivity Inducing Factor) is a protein complex that can either negatively or positively affect transcription by RNA polymerase II (Pol II).[2] It can interact with the negative elongation factor (NELF) to promote the stalling of Pol II at some genes, which is called promoter proximal pausing.[3] The pause occurs soon after initiation, once 20-60 nucleotides have been transcribed.[3] This stalling is relieved by positive transcription elongation factor b (P-TEFb) and Pol II enters productive elongation to resume synthesis till finish.[1] In humans, DSIF is composed of hSPT4 and hSPT5.[2] hSPT5 has a direct role in mRNA capping which occurs while the elongation is paused. [4]

SPT5 is preserved in humans to bacteria.[5] SPT4 and SPT5 in yeast are the homologs of hSPT4 and hSPT5.[2][6] In bacteria, the homologous complex only contains NusG, a Spt5 homolog.[7] Archaea have both proteins.[8]

The complex locks the RNA polymerase (RNAP) clamp into a closed state to prevent the elongation complex (EC) from dissociating. The Spt5 NGN domain helps anneal the two strands of DNA upstream. The single KOW domain in bacteria and archaea anchors a ribosome to the RNAP.[8]

Role in Diseases

HIV

DSIF plays the same role for HIV-1 gene expression as it would normally in transcription.[9][10] This is because P-TEFb phosphorylates DSIF the same regardless of whether or not P-TEFb goes through normal cellular regulation or bypasses it due to Tat.[11]

References

  1. 1 2 Zhou, Qiang; Li, Tiandao; Price, David H. (2012-07-07). "RNA Polymerase II Elongation Control". Annual Review of Biochemistry. 81 (1): 119–143. doi:10.1146/annurev-biochem-052610-095910. ISSN 0066-4154. PMC 4273853.
  2. 1 2 3 Wada T, Takagi T, Yamaguchi Y, Ferdous A, Imai T, Hirose S, et al. (February 1998). "DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs". Genes & Development. 12 (3): 343–356. doi:10.1101/gad.12.3.343. PMC 316480. PMID 9450929.
  3. 1 2 Tettey, Theophilus T.; Gao, Xin; Shao, Wanqing; Li, Hua; Story, Benjamin A.; Chitsazan, Alex D.; Glaser, Robert L.; Goode, Zach H.; Seidel, Christopher W.; Conaway, Ronald C.; Zeitlinger, Julia; Blanchette, Marco; Conaway, Joan W. (2019-06-25). "A Role for FACT in RNA Polymerase II Promoter-Proximal Pausing". Cell Reports. 27 (13): 3770–3779.e7. doi:10.1016/j.celrep.2019.05.099.
  4. ↑ Wen, Y.; Shatkin, A. J. (1999-07-15). "Transcription elongation factor hSPT5 stimulates mRNA capping". Genes & Development. 13 (14): 1774–1779. doi:10.1101/gad.13.14.1774. ISSN 0890-9369. PMC 316881.
  5. ↑ Decker, Tim-Michael (2021-07-09). "Mechanisms of Transcription Elongation Factor DSIF (Spt4–Spt5)". Journal of Molecular Biology. 433 (14): 166657. doi:10.1016/j.jmb.2020.09.016.
  6. ↑ Wenzel, Sabine; Schweimer, Kristian; Rösch, Paul; Wöhrl, Birgitta M. (2008-06-06). "The small hSpt4 subunit of the human transcription elongation factor DSIF is a Zn-finger protein with α/β type topology". Biochemical and Biophysical Research Communications. 370 (3): 414–418. doi:10.1016/j.bbrc.2008.03.080.
  7. ↑ Yakhnin, Alexander V.; Murakami, Katsuhiko S.; Babitzke, Paul (2016-03-04). "NusG Is a Sequence-specific RNA Polymerase Pause Factor That Binds to the Non-template DNA within the Paused Transcription Bubble". Journal of Biological Chemistry. 291 (10): 5299–5308. doi:10.1074/jbc.M115.704189. PMC 4777861.
  8. 1 2 Fouqueau T, Blombach F, Cackett G, Carty AE, Matelska DM, Ofer S, et al. (December 2018). "The cutting edge of archaeal transcription". Emerging Topics in Life Sciences. 2 (4): 517–533. doi:10.1042/ETLS20180014. PMC 7289017. PMID 33525828.
  9. ↑ Zhang, Zhiqiang; Klatt, Alicia; Gilmour, David S.; Henderson, Andrew J. (2007-06-08). "Negative Elongation Factor NELF Represses Human Immunodeficiency Virus Transcription by Pausing the RNA Polymerase II Complex". Journal of Biological Chemistry. 282 (23): 16981–16988. doi:10.1074/jbc.M610688200.
  10. ↑ Ping, Yueh-Hsin; Rana, Tariq M. (2001-04-20). "DSIF and NELF Interact with RNA Polymerase II Elongation Complex and HIV-1 Tat Stimulates P-TEFb-mediated Phosphorylation of RNA Polymerase II and DSIF during Transcription Elongation". Journal of Biological Chemistry. 276 (16): 12951–12958. doi:10.1074/jbc.M006130200.
  11. ↑ Zhu, Yuerong; Pe’ery, Tsafrira; Peng, Junmin; Ramanathan, Yegnanarayana; Marshall, Nick; Marshall, Tricia; Amendt, Brad; Mathews, Michael B.; Price, David H. (1997-10-15). "Transcription elongation factor P-TEFb is required for HIV-1 Tat transactivation in vitro". Genes & Development. 11 (20): 2622–2632. doi:10.1101/gad.11.20.2622. ISSN 0890-9369. PMC 316609.
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