Negative elongation factor

In molecular biology, the NELF (negative elongation factor) is a four-subunit protein complex (NELF-A, NELF-B, NELF-C/NELF-D, and NELF-E) that negatively impacts transcription by RNA polymerase II (Pol II) by pausing about 20-60 nucleotides downstream from the transcription start site (TSS).[1][2]

Protein structure of the E subunit of the negative elongation factor (NELF-E).

Structure

The NELF has four subunits within its complex which are the following: NELF-A, NELF-B, NELF-C/NELF-D, and NELF-E. [2] The NELF-A subunit is encoded by the gene WHSC2 (Wolf-Hirschhorn syndrome candidate 2).[3] Micro-sequencing analysis demonstrated that NELF-B was the protein previously identified as being encoded by the gene COBRA1. It is unknown whether or not NELF-C and NELF-D are peptides resulting from the same mRNA with different translation initiation sites; possibly differing only in an extra 9 amino acids for NELF-C at the N-terminus, or peptides from different mRNAs entirely. A single NELF complex consists of either NELF-C or NELF-D, but not both. NELF-E is also known as RDBP.[1][4]

Function and Interactions

NELF is located in the nucleus. NELF binds in a stable complex with DSIF (5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB)-sensitivity inducing factor) and RNA polymerase II together, but not with either alone. Due to its role in transcription, NELF is also a key player in the negative function of DSIF.[5]NELF also works with DSIF to inhibit the speed of Pol II during the elongation phase in transcription.[5] In D. melanogaster, the HSP70 gene is affected by NELF and DSIF through the induction of promoter proximal pausing.[5] It is thought that NELF arose to assist DSIF by amplifying its negative effects in order to increase gene expression control.[5] P-TEFb (positive transcription elongation factor b) inhibits the effect of NELF and DSIF on Pol II elongation, via its phosphorylation of serine-2 of the C-terminal domain of Pol II, and the SPT5 subunit of DSIF, causing dissociation of NELF.[1] However, many mechanisms by which NELF and DSIF operate remain unclear.[5] NELF homologues exist in some metazoans (e.g. insects and vertebrates) but have not been found in plants, yeast, or nematodes (worms).[1][5]

Interactions by subunit:

NELF-A: Pol II complex.[3]

NELF-B: KIAA1191, NELF-E, and an early sequence of BRCA1.[6]

NELF-C/D: ARAF1, PCF11, and KAT8.[7]

NELF-E: NELF-B and HIV TAR RNA.[8]

Clinical Significance

The NELF complex is also possibly a player in the enlistment of gene PCF11 to the stopped Pol II in HIV-1 latency.[7] NELF-A may play a role in the phenotype of Wolf-Hirschhorn syndrome (WHS) as it is mapped to the critical area of deletion on the short arm of chromosome 4.[3][9] Pol II pausing controlled by NELF is a key source of R-loop aggregation in mammary epithelial cells that are BRCA1-deficient, which could ultimately lead to tumorigenesis.[10]

References
  1. Adelman K, Lis JT (October 2012). "Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans". Nature Reviews. Genetics. 13 (10): 720–31. doi:10.1038/nrg3293. PMC 3552498. PMID 22986266.
  2. Aoi Y, Smith ER, Shah AP, Rendleman EJ, Marshall SA, Woodfin AR, et al. (April 2020). "NELF Regulates a Promoter-Proximal Step Distinct from RNA Pol II Pause-Release". Molecular Cell. 78 (2): 261–274.e5. doi:10.1016/j.molcel.2020.02.014. PMC 7402197. PMID 32155413.
  3. "NELFA negative elongation factor complex member A [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-11-15.
  4. Narita T, Yamaguchi Y, Yano K, Sugimoto S, Chanarat S, Wada T, et al. (March 2003). "Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex". Molecular and Cellular Biology. 23 (6): 1863–73. doi:10.1128/MCB.23.6.1863-1873.2003. PMC 149481. PMID 12612062.
  5. Peterlin BM, Price DH (August 2006). "Controlling the elongation phase of transcription with P-TEFb". Molecular Cell. 23 (3): 297–305. doi:10.1016/j.molcel.2006.06.014. PMID 16885020.
  6. ""NELFB - Negative elongation factor B - Homo sapiens (Human) - NELFB gene & protein"".
  7. ""NELFCD - Negative elongation factor C/D - Homo sapiens (Human) - NELFCD gene & protein"".
  8. ""NELFE - Negative elongation factor E - Homo sapiens (Human) - NELFE gene & protein"".
  9. Kerzendorfer C, Hannes F, Colnaghi R, Abramowicz I, Carpenter G, Vermeesch JR, O'Driscoll M (May 2012). "Characterizing the functional consequences of haploinsufficiency of NELF-A (WHSC2) and SLBP identifies novel cellular phenotypes in Wolf-Hirschhorn syndrome". Human Molecular Genetics. 21 (10): 2181–93. doi:10.1093/hmg/dds033. PMID 22328085.
  10. Zhang X, Chiang HC, Wang Y, Zhang C, Smith S, Zhao X, et al. (March 2018). "Author Correction: Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis". Nature Communications. 9 (1): 16211. doi:10.1038/ncomms16211. PMC 5882462. PMID 29600804.


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