Alternative titles; symbols
HGNC Approved Gene Symbol: TENT4A
Cytogenetic location: 5p15.31 Genomic coordinates (GRCh38): 5:6,713,432-6,757,044 (from NCBI)
Walowsky et al. (1999) cloned the human homologs of yeast TRF4 and designated them TRF4-1 and TRF4-2 (605540). One clone (TRF4-1) contained an insert encoding a potential TRF4-related open reading frame of 517 amino acids with a potential initiator methionine at position 41. The sequence included all the regions of high evolutionary conservation in the TRF4 gene family. Saccharomyces cerevisiae and human TRF4-1 are 39% identical over 310 amino acids in the central region of both proteins.
Wang et al. (2000) found that yeast TRF4, an evolutionarily conserved gene necessary for chromosome segregation, encodes a DNA polymerase with beta-polymerase-like properties. A double mutant in the redundant homologs TRF4 and TRF5 is unable to complete S phase, whereas a TRF4 single mutant completes a presumably defective S phase that results in the failure of cohesion between the replicated sister chromatids. This suggested that TRFs are a key link in the coordination between DNA replication and sister chromatid cohesion.
Lim et al. (2018) identified TENT4A and TENT4B (605540) as the enzymes responsible for mRNA guanylation. Purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues, the most common of which is guanosine. A single guanosine residue is sufficient to impede the deadenylase CCR4-NOT complex (see CNOT1, 604917), which trims the tail and exposes guanosine at the 3-prime end. Consistently, depletion of TENT4A and TENT4B leads to a decrease in mRNA half-life and abundance in cells. Lim et al. (2018) concluded that TENT4A and TENT4B produce a mixed tail that shields mRNA from rapid deadenylation.
Using a knockout screen in HepG2 cells, Hyrina et al. (2019) identified ZCCHC14 (620697) as a host factor required for transcription of hepatitis B virus (HBV) and expression of HBV surface antigen (HBsAg). Analysis with RG7834, a small molecule inhibitor of HBV replication, revealed that ZCCHC14, TENT4B, and PARP10 (609564) were involved in RG7834 activity, and that RG7834 inhibited TENT4B polymerase/polyadenylation activity. ZCCHC14 worked in conjunction with TENT4A and TENT4B to stabilize HBsAg expression through RNA tailing. ZCCHC14 formed a complex with TENT4B and the HBV posttranscriptional regulatory element (PRE), and RG7834 inhibited TENT4A/TENT4B enzymatic activity within the ZCCHC14-HBV PRE complex. ZCCHC14, likely in complex with TENT4A/TENT4B, promoted expression of HBsAg through stem-loop-alpha within the 5-prime end of the HBV PRE.
Kim et al. (2020) found that HepG2.2.15 cells incorporated with HBV DNA and primary human foreskin fibroblasts infected with human cytomegalovirus (HCMV) had extensive mixed tailing of viral RNAs. Gene depletion indicated that viral RNA tailing was mediated by TENT4A and TENT4B, the same enzymes that contribute to host-cell mRNA tailing. Analysis with HepG2.2.15 cells revealed that HBV mRNAs were major mRNA substrates of TENT4A/TENT4B, and that TENT4A/TENT4B interacted with HBV mRNAs through the HBV PRE region. Stem-loop-alpha of the HBV PRE was essential for regulation of posttranscriptional HBV RNA tailing by TENT4A/TENT4B, and HCMV RNA2.7 harbored a similar stem-loop that was responsible for regulation of RNA tailing by TENT4A/TENT4B. Further analysis identified ZCCHC14 as a cofactor that recognized the stem-loop structures of HBV and HCMV. As a SAM domain-containing protein, ZCCHC14 interacted with TENT4A and TENT4B mainly in the cytoplasm in an RNA-independent manner and regulated viral RNA tailing by binding to the viral stem-loop structure to protect the viral RNAs from decay by preventing their deadenylation.
By knockout analysis, Li et al. (2022) demonstrated that ZCCHC14 was required for replication of hepatitis A virus (HAV) in host cells. Like HBV, HAV replication also required TENT4A and TENT4B, but the mechanism to regulate viral replication by ZCCHC14/TENT4 complex appeared to differ for HBV and HAV, as the ZCCHC14/TENT4 complex regulated HAV RNA synthesis, but not RNA tailing. ZCCHC14 mainly bound stem-loop Vb within the 5-prime UTR of HAV and recruited TENT4A. RG7834 did not affect RNA tailing of HAV, but it disrupted interaction between ZCCHC14 and TENT4A/TENT4B and affected viral RNA synthesis, thereby leading to reduced HAV replication. Moreover, RG7834 ablated HAV replication and reversed liver inflammation in a mouse model of hepatitis A in vivo, although extended treatment was likely required to prevent virologic relapse in immunocompromised mice. Further analysis suggested that RG7834 might be useful for chemoprevention of HAV when administered immediately after virus challenge.
Walowsky et al. (1999) noted that a region of the human PAPD7 (TRF4-1) gene is identical to an STS (G06245) mapping to 5p15. This region of chromosome 5p is among the most common regions amplified in small cell lung tumor cell lines and in primary small cell tumors. In addition, amplifications in this region are frequently found in high-grade ovarian tumors.
Hyrina, A., Jones, C., Chen, D., Clarkson, S., Cochran, N., Feucht, P., Hoffman, G., Lindeman, A., Russ, C., Sigoillot, F., Tsang, T., Uehara, K., Xie, L., Ganem, D., Holdorf, M. A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production. Cell Rep. 29: 2970-2978, 2019. [PubMed: 31801065] [Full Text: https://doi.org/10.1016/j.celrep.2019.10.113]
Kim, D., Lee, Y. S., Jung, S. J., Yeo, J., Seo, J. J., Lee, Y. Y., Lim, J., Chang, H., Song, J., Yang, J., Kim, J. S., Jung, G., Ahn, K., Kim, V. N. Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing. Nature Struct. Molec. Biol. 27: 581-588, 2020. [PubMed: 32451488] [Full Text: https://doi.org/10.1038/s41594-020-0427-3]
Li, Y., Misumi, I., Shiota, T., Sun, L., Lenarcic, E. M., Kim, H., Shirasaki, T., Hertel-Wulff, A., Tibbs, T., Mitchell, J. E., McKnight, K. L., Cameron, C. E., Moorman, N. J., McGivern, D. R., Cullen, J. M., Whitmire, J. K., Lemon, S. M. The ZCCHC14/TENT4 complex is required for hepatitis A virus RNA synthesis. Proc. Nat. Acad. Sci. 119: e2204511119, 2022. [PubMed: 35867748] [Full Text: https://doi.org/10.1073/pnas.2204511119]
Lim, J., Kim, D., Lee, Y. S., Ha, M., Lee, M., Yeo, J., Chang, H., Song, J., Ahn, K., Kim, V. N. Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation. Science 361: 701-704, 2018. [PubMed: 30026317] [Full Text: https://doi.org/10.1126/science.aam5794]
Walowsky, C., Fitzhugh, D. J., Castano, I. B., Ju, J. Y., Levin, N. A., Christman, M. F. The topoisomerase-related function gene TRF4 affects cellular sensitivity to the antitumor agent camptothecin. J. Biol. Chem. 274: 7302-7308, 1999. [PubMed: 10066793] [Full Text: https://doi.org/10.1074/jbc.274.11.7302]
Wang, Z., Castano, I. B., De Las Penas, A., Adams, C., Christman, M. F. Pol kappa: a DNA polymerase required for sister chromatid cohesion. Science 289: 774-779, 2000. [PubMed: 10926539] [Full Text: https://doi.org/10.1126/science.289.5480.774]