Alternative titles; symbols
HGNC Approved Gene Symbol: NELFA
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38) : 4:1,982,723-2,008,974 (from NCBI)
NELFA is a subunit of negative elongation factor (NELF), which also includes NELFB (611180), either NELFC or NELFD (NELFCD; 605297), and NELFE (154040). NELF acts with DRB sensitivity-inducing factor (DSIF), a heterodimer of SPT4 (SUPT4H1; 603555) and SPT5 (SUPT5H; 602102), to cause transcriptional pausing of RNA polymerase II (see 180660) (Narita et al., 2003).
Wolf-Hirschhorn syndrome (WHS; 194190) is a contiguous gene syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). To identify genes that may contribute to this phenotype, Wright et al. (1997) generated a transcript map of the 165-kb critical region and identified a number of potential genes. By analyzing a partial clone from this region, Wright et al. (1999) characterized a novel gene, which they designated Wolf-Hirschhorn syndrome candidate-2. WHSC2 encodes a deduced 528-amino acid protein with a predicted molecular mass of 57 kD. It contains a hydrophilic N terminus followed by a transmembrane region and a hydrophilic C terminus, and has 2 predicted nuclear localization signals. Northern blot analysis detected ubiquitous expression of a 2.4-kb transcript with a reduced level in adult lung relative to other tissues and higher levels in fetal than in adult tissues. Wright et al. (1999) also cloned mouse Whsc2 and determined that the deduced protein shares 93.3% sequence identity with the human protein and has a similar pattern of expression. In situ hybridization to mouse embryonic tissues revealed ubiquitous expression from 10.5 to 13.5 dpc. In an addendum, Wright et al. (1999) cited a personal communication from Y. Yamaguchi suggesting that the WHSC2 gene is a member of the NELF complex described by Yamaguchi et al. (1999); see 154040.
NELFA shows limited sequence similarity to hepatitis delta antigen, the viral protein required for replication of hepatitis delta virus. Yamaguchi et al. (2001) showed that the hepatitis delta antigen binds RNA polymerase II directly and stimulates transcription by displacing NELF and promoting RNA polymerase II elongation. Yamaguchi et al. (2001) concluded that their results suggest that hepatitis delta antigen may regulate RNA polymerase II elongation during both cellular mRNA synthesis and hepatitis delta virus RNA replication.
Narita et al. (2003) reconstituted an active NELF-like complex by overexpressing epitope-tagged NELFA, NELFB, NELFD, and NELFE in insect cells. They found that NELFB and NELFE interacted directly and that NELFD interacted directly with NELFA and NELFB, consistent with a model in which NELFB and NELFD (or NELFC) bring NELFA and NELFE together via 3 protein-protein interactions. All 4 NELF subunits were required for NELF function. NELFA was essential, but not sufficient, for NELF to cooperate with DSIF and repress transcriptional elongation.
Narita et al. (2007) showed that NELF interacted with the nuclear cap-binding complex (CBC), which plays roles in several mRNA processing steps. The interaction was mediated by NELFE and the CBC subunit CBP80 (NCBP1; 600469). Small interfering RNA-mediated knockdown of NELFE or CBP80 in HeLa cells reduced the protein levels of other NELF and CBC subunits, respectively, suggesting that free NELF and CBC subunits are unstable in the absence of the functional holocomplexes. Knockdown of NELFE or CBP80 also resulted in elevated levels of polyadenylated histone mRNAs. Chromatin immunoprecipitation analysis demonstrated that NELF and CBC associated with both the 5-prime and 3-prime regions of replication-dependent histone genes. Immunofluorescence and FISH localized NELF in HeLa cell nuclei, where it often colocalized with histone loci and Cajal bodies, and with cleavage bodies during S phase. Narita et al. (2007) concluded that NELF functions in histone mRNA maturation by associating with histone gene loci, Cajal bodies, and cleavage bodies in a temporally and spatially coordinated manner.
Narita, T., Yamaguchi, Y., Yano, K., Sugimoto, S., Chanarat, S., Wada, T., Kim, D., Hasegawa, J., Omori, M., Inukai, N., Endoh, M., Yamada, T., Handa, H. Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex. Molec. Cell. Biol. 23: 1863-1873, 2003. [PubMed: 12612062] [Full Text: https://doi.org/10.1128/MCB.23.6.1863-1873.2003]
Narita, T., Yung, T. M. C., Yamamoto, J., Tsuboi, Y., Tanabe, H., Tanaka, K., Yamaguchi, Y., Handa, H. NELF interacts with CBC and participates in 3-prime end processing of replication-dependent histone mRNAs. Molec. Cell 26: 349-365, 2007. [PubMed: 17499042] [Full Text: https://doi.org/10.1016/j.molcel.2007.04.011]
Wright, T. J., Costa, J. L., Naranjo, C., Francis-West, P., Altherr, M. R. Comparative analysis of a novel gene from the Wolf-Hirschhorn/Pitt-Rogers-Danks syndrome critical region. Genomics 59: 203-212, 1999. [PubMed: 10409432] [Full Text: https://doi.org/10.1006/geno.1999.5871]
Wright, T. J., Ricke, D. O., Denison, K., Abmayr, S., Cotter, P. D., Hirschhorn, K., Keinanen, M., McDonald-McGinn, D., Somer, M., Spinner, N., Yang-Feng, T., Zackai, E., Altherr, M. R. A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum. Molec. Genet. 6: 317-324, 1997. [PubMed: 9063753] [Full Text: https://doi.org/10.1093/hmg/6.2.317]
Yamaguchi, Y., Filipovska, J., Yano, K., Furuya, A., Inukai, N., Narita, T., Wada, T., Sugimoto, S., Konarska, M. M., Handa, H. Stimulation of RNA polymerase II elongation by hepatitis delta antigen. Science 293: 124-127, 2001. [PubMed: 11387440] [Full Text: https://doi.org/10.1126/science.1057925]
Yamaguchi, Y., Takagi, T., Wada, T., Yano, K., Furuya, A., Sugimoto, S., Hasegawa, J., Handa, H. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 97: 41-51, 1999. [PubMed: 10199401] [Full Text: https://doi.org/10.1016/s0092-8674(00)80713-8]