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]
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 geneWHSC2 (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]
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]
The NELF complex is also possibly a player in the enlistment of gene PCF11 to the stopped Pol II in HIV-1 latency.[10] 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][13] 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.[14]