DSIF

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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. RNA polymerase II elongation control.jpg
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.

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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">RNA polymerase II</span> Protein complex that transcribes DNA

RNA polymerase II is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic cells. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. A wide range of transcription factors are required for it to bind to upstream gene promoters and begin transcription.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

<span class="mw-page-title-main">P-TEFb</span>

The positive transcription elongation factor, P-TEFb, is a multiprotein complex that plays an essential role in the regulation of transcription by RNA polymerase II in eukaryotes. Immediately following initiation Pol II becomes trapped in promoter proximal paused positions on the majority of human genes. P-TEFb is a cyclin dependent kinase that can phosphorylate the DRB sensitivity inducing factor (DSIF) and negative elongation factor (NELF), as well as the carboxyl terminal domain of the large subunit of Pol II and this causes the transition into productive elongation leading to the synthesis of mRNAs. P-TEFb is regulated in part by a reversible association with the 7SK snRNP. Treatment of cells with the P-TEFb inhibitors DRB or flavopidirol leads to loss of mRNA production and ultimately cell death.

<span class="mw-page-title-main">Cyclin-dependent kinase 9</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.

<span class="mw-page-title-main">POLR2A</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerase II subunit RPB1, also known as RPB1, is an enzyme that is encoded by the POLR2A gene in humans.

<span class="mw-page-title-main">Cyclin T1</span> Protein-coding gene in humans

Cyclin-T1 is a protein that in humans is encoded by the CCNT1 gene.

<span class="mw-page-title-main">RNA polymerase II subunit B4</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerase II subunit RPB4 is an enzyme that in humans is encoded by the POLR2D gene.

<span class="mw-page-title-main">SUPT5H</span> Protein-coding gene in the species Homo sapiens

Transcription elongation factor SPT5 is a protein that in humans is encoded by the SUPT5H gene.

<span class="mw-page-title-main">TCEA1</span> Human protein-coding gene

Transcription elongation factor A protein 1 is a protein that in humans is encoded by the TCEA1 gene.

<span class="mw-page-title-main">RDBP</span> Protein

Negative elongation factor E is a protein that in humans is encoded by the RDBP gene.

<span class="mw-page-title-main">Cofactor of BRCA1</span> Protein-coding gene in humans

Cofactor of BRCA1, also known as COBRA1, is a human gene that encodes NELF-B.

<span class="mw-page-title-main">SUPT4H1</span> Protein-coding gene in the species Homo sapiens

Transcription elongation factor SPT4 is a protein that in humans is encoded by the SUPT4H1 gene.

<span class="mw-page-title-main">WHSC2</span> Protein-coding gene in the species Homo sapiens

Negative elongation factor A is a protein that in humans is encoded by the WHSC2 gene.

<span class="mw-page-title-main">TH1L</span> Protein-coding gene in the species Homo sapiens

Negative elongation factor C/D is a protein that in humans is encoded by the TH1L gene.

<span class="mw-page-title-main">CTDSPL</span> Protein-coding gene in the species Homo sapiens

CTD small phosphatase-like protein is an enzyme that in humans is encoded by the CTDSPL gene.

<span class="mw-page-title-main">GTF2F2</span> Protein-coding gene in the species Homo sapiens

General transcription factor IIF subunit 2 is a protein that in humans is encoded by the GTF2F2 gene.

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

<span class="mw-page-title-main">Negative elongation factor</span> Protein

In molecular biology, the NELF is a four-subunit protein complex that negatively impacts transcription by RNA polymerase II by pausing about 20-60 nucleotides downstream from the transcription start site (TSS).

Tat (HIV)

In molecular biology, Tat is a protein that is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101 amino acids depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.

<span class="mw-page-title-main">Archaeal transcription</span>

Archaeal transcription is the process in which a segment of archaeal DNA is copied into a newly synthesized strand of RNA using the sole Pol II-like RNA polymerase (RNAP). The process occurs in three main steps: initiation, elongation, and termination; and the end result is a strand of RNA that is complementary to a single strand of DNA. A number of transcription factors govern this process with homologs in both bacteria and eukaryotes, with the core machinery more similar to eukaryotic transcription.

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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