Vol. 3 No. 4

Review Articles

Abnormal Expression of Transcription Factor IIIA in Tumors and Target Therapy Potential Application for Transcription Factor IIIA

Published 2026-07-31

  • Jing Wang
    • ,
  • Faqing Tang

Jing Wang
Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University & Hunan Cancer Hospital , The Central Hospital of Xiangtan

Faqing Tang
Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University & Hunan Cancer Hospital

Abstract

Transcription factor III a (TFIIIA), as one of the specific transcription factor members of RNA polymerase III, plays an important role in guiding the transcription of 5S rRNA genes by RNA polymerase III. This article elaborates on the special structure and function of TFIIIA, and introduces the synergistic effect of homologous transcription factors TFIIIB and TFIIIC in the process of 5S rRNA gene transcription guided by RNA polymerase III. It also discusses the relationship between RNA polymerase III transcription activity and the product 5SrRNA and the occurrence and development of tumors. The abnormal expression of most transcription factors is involved in the occurrence and development of various cancers, and 20% of the oncogenes discovered are transcription factors. In order to explore the transcription factor TFIIIA as a tumor therapy target, this article probe the strategy in which transcription factors are used as tumor therapy targets based on discussing TFIIIA structure and function, including its expression and degradation, interaction with cofactors/proteins, and dynamic changes in its binding to DNA.

Keywords

Transcription factor, TFIIIA, 5S rRNA, Tumor, Target therapy

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References

  1. Engelke, D.R., et al.,Specific interaction of a purified transcription factor with an internal control region of 5S RNA genes.Cell, 1980.19(3): p. 717-28. https://doi.org/10.1016/S0092-8674(80)80048-1
  2. Arakawa, H., et al.,Molecular cloning, characterization, and chromosomal mapping of a novel human gene (GTF3A) that is highly homologous to Xenopus transcription factor IIIA.Cytogenet Cell Genet, 1995.70(3-4): p. 235-8. https://doi.org/10.1159/000134041
  3. Mathieu, O., et al.,Identification and characterization of transcription factor IIIA and ribosomal protein L5 from Arabidopsis thaliana.Nucleic Acids Res, 2003.31(9): p. 2424-33. https://doi.org/10.1093/nar/gkg335
  4. Hanas, J.S., et al.,cDNA cloning, DNA binding, and evolution of mammalian transcription factor IIIA.Gene, 2002.282(1-2): p. 43-52.
  5. Layat, E., A.V. Probst, and S. Tourmente,Structure, function and regulation of Transcription Factor IIIA: From Xenopus to Arabidopsis.Biochim Biophys Acta, 2013.1829(3-4): p. 274-82. https://doi.org/10.1016/j.bbagrm.2012.10.013
  6. Shastry, B.S.,Transcription factor IIIA (TFIIIA) in the second decade.J Cell Sci, 1996.109 ( Pt 3): p. 535-9.
  7. Birkenmeier, E.H., D.D. Brown, and E. Jordan,A nuclear extract of Xenopus laevis oocytes that accurately transcribes 5S RNA genes.Cell, 1978.15(3): p. 1077-86. https://doi.org/10.1016/0092-8674(78)90291-X
  8. Darsillo, P. and P.W. Huber,The use of chemical nucleases to analyze RNA-protein interactions. The TFIIIA-5 S rRNA complex.J Biol Chem, 1991.266(31): p. 21075-82.
  9. Fairall, L. and D. Rhodes,A new approach to the analysis of DNase I footprinting data and its application to the TFIIIA/5S DNA complex.Nucleic Acids Res, 1992.20(18): p. 4727-31. https://doi.org/10.1093/nar/20.18.4727
  10. Del Rio, S. and D.R. Setzer,The role of zinc fingers in transcriptional activation by transcription factor IIIA.Proc Natl Acad Sci U S A, 1993.90(1): p. 168-72. https://doi.org/10.1073/pnas.90.1.168
  11. Theunissen, O., et al.,RNA and DNA binding zinc fingers in Xenopus TFIIIA.Cell, 1992.71(4): p. 679-90. https://doi.org/10.1016/0092-8674(92)90601-8
  12. Ryan, R.F. and M.K. Darby,The role of zinc finger linkers in p43 and TFIIIA binding to 5S rRNA and DNA.Nucleic Acids Res, 1998.26(3): p. 703-9. https://doi.org/10.1093/nar/26.3.703
  13. Shastry, B.S.,Transcription factor IIIA (TFIIIA): an update.Experientia, 1993.49(10): p. 831-5. https://doi.org/10.1007/BF01952592
  14. Theunissen, O., F. Rudt, and T. Pieler,Structural determinants in 5S RNA and TFIIIA for 7S RNP formation.Eur J Biochem, 1998.258(2): p. 758-67. https://doi.org/10.1046/j.1432-1327.1998.2580758.x
  15. Bieker, J.J., P.L. Martin, and R.G. Roeder,Formation of a rate-limiting intermediate in 5S RNA gene transcription.Cell, 1985.40(1): p. 119-27. https://doi.org/10.1016/0092-8674(85)90315-0
  16. Seifart, K.H., et al.,Purification of human transcription factor IIIA and its interaction with a chemically synthesized gene encoding human 5 S rRNA.J Biol Chem, 1989.264(3): p. 1702-9.
  17. Weser, S., et al.,Assembly and isolation of intermediate steps of transcription complexes formed on the human 5S rRNA gene.Nucleic Acids Res, 2003.31(9): p. 2408-16. https://doi.org/10.1093/nar/gkg318
  18. Fu, Y., et al.,Alternative splicing of anciently exonized 5S rRNA regulates plant transcription factor TFIIIA.Genome Res, 2009.19(5): p. 913-21. https://doi.org/10.1101/gr.087197.108
  19. Layat, E., et al.,Transcript levels, alternative splicing and proteolytic cleavage of TFIIIA control 5S rRNA accumulation during Arabidopsis thaliana development.Plant J, 2012.71(1): p. 35-44. https://doi.org/10.1111/j.1365-313X.2012.05008.x
  20. Cassiday, L.A. and L.J. Maher, 3rd,Having it both ways: transcription factors that bind DNA and RNA.Nucleic Acids Res, 2002.30(19): p. 4118-26. https://doi.org/10.1093/nar/gkf535
  21. Laferté, A., et al., The transcriptional activity of RNA polymerase I is a key determinant for the level of all ribosome components. Genes Dev, 2006. 20(15): p. 2030-40. https://doi.org/10.1101/gad.386106
  22. Johnson, S.A., et al., Increased expression of TATA-binding protein, the central transcription factor, can contribute to oncogenesis. Mol Cell Biol, 2003. 23(9): p. 3043-51. https://doi.org/10.1128/MCB.23.9.3043-3051.2003
  23. Zhong, S., J. Fromm, and D.L. Johnson, TBP is differentially regulated by c-Jun N-terminal kinase 1 (JNK1) and JNK2 through Elk-1, controlling c-Jun expression and cell proliferation. Mol Cell Biol, 2007. 27(1): p. 54-64. https://doi.org/10.1128/MCB.01365-06
  24. Johnson, S.A.S., et al., Elevated TATA-binding protein expression drives vascular endothelial growth factor expression in colon cancer. Oncotarget, 2017. 8(30): p. 48832-48845. https://doi.org/10.18632/oncotarget.16384
  25. Zhong, Q., et al., Tamoxifen represses alcohol-induced transcription of RNA polymerase III-dependent genes in breast cancer cells. Oncotarget, 2014. 5(23): p. 12410-7. https://doi.org/10.18632/oncotarget.2678
  26. Yi, Y., et al., Exploring a common mechanism of alcohol-induced deregulation of RNA Pol III genes in liver and breast cells. Gene, 2017. 626: p. 309-318. https://doi.org/10.1016/j.gene.2017.05.048
  27. Zhong, Q., et al., The significance of Brf1 overexpression in human hepatocellular carcinoma. Oncotarget, 2016. 7(5): p. 6243-54. https://doi.org/10.18632/oncotarget.6668
  28. Gouge, J., et al., Molecular mechanisms of Bdp1 in TFIIIB assembly and RNA polymerase III transcription initiation. Nat Commun, 2017. 8(1): p. 130. https://doi.org/10.1038/s41467-017-00126-1
  29. Román-Carraro, F.C., et al., TFIIIB Subunit Bdp1 Participates in RNA Polymerase III Transcription in the Protozoan Parasite Leishmania major. Biomed Res Int, 2019. 2019: p. 1425281. https://doi.org/10.1155/2019/1425281
  30. Male, G., et al., Architecture of TFIIIC and its role in RNA polymerase III pre-initiation complex assembly. Nat Commun, 2015. 6: p. 7387. https://doi.org/10.1038/ncomms8387
  31. Kantidakis, T., et al., mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci U S A, 2010. 107(26): p. 11823-8. https://doi.org/10.1073/pnas.1005188107
  32. Graczyk, D., M. Cieśla, and M. Boguta, Regulation of tRNA synthesis by the general transcription factors of RNA polymerase III - TFIIIB and TFIIIC, and by the MAF1 protein. Biochim Biophys Acta Gene Regul Mech, 2018. 1861(4): p. 320-329. https://doi.org/10.1016/j.bbagrm.2018.01.011
  33. Szymanski, M., et al., 5 S rRNA: structure and interactions. Biochem J, 2003. 371(Pt 3): p. 641-51. https://doi.org/10.1042/BJ20020872
  34. Slimane, S.N., et al., Ribosome Biogenesis Alterations in Colorectal Cancer. Cells, 2020. 9(11). https://doi.org/10.3390/cells9112361
  35. Ciganda, M. and N. Williams, Eukaryotic 5S rRNA biogenesis. Wiley Interdiscip Rev RNA, 2011. 2(4): p. 523-33. https://doi.org/10.1002/wrna.74
  36. Miliani de Marval, P.L. and Y. Zhang, The RP-Mdm2-p53 pathway and tumorigenesis. Oncotarget, 2011. 2(3): p. 234-8. https://doi.org/10.18632/oncotarget.228
  37. Liu, Y., et al., Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation. Proc Natl Acad Sci U S A, 2014. 111(23): p. E2414-22. https://doi.org/10.1073/pnas.1315605111
  38. Sloan, K.E., M.T. Bohnsack, and N.J. Watkins, The 5S RNP couples p53 homeostasis to ribosome biogenesis and nucleolar stress. Cell Rep, 2013. 5(1): p. 237-47. https://doi.org/10.1016/j.celrep.2013.08.049
  39. Onofrillo, C., et al., The pre-existing population of 5S rRNA effects p53 stabilization during ribosome biogenesis inhibition. Oncotarget, 2017. 8(3): p. 4257-4267. https://doi.org/10.18632/oncotarget.13833
  40. Neely, L.S., et al., Identification of a minimal domain of 5 S ribosomal RNA sufficient for high affinity interactions with the RNA-specific zinc fingers of transcription factor IIIA. J Mol Biol, 1999. 291(3): p. 549-60. https://doi.org/10.1006/jmbi.1999.2985
  41. Roy, N. and M. Hebrok, Regulation of Cellular Identity in Cancer. Dev Cell, 2015. 35(6): p. 674-84. https://doi.org/10.1016/j.devcel.2015.12.001
  42. Huilgol, D., et al., Transcription Factors That Govern Development and Disease: An Achilles Heel in Cancer. Genes (Basel), 2019. 10(10). https://doi.org/10.3390/genes10100794
  43. Lim, J.H., et al., Chromosomal protein HMGN1 modulates histone H3 phosphorylation. Mol Cell, 2004. 15(4): p. 573-84. https://doi.org/10.1016/j.molcel.2004.08.006
  44. Tepass, U., C. Theres, and E. Knust, crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell, 1990. 61(5): p. 787-99. https://doi.org/10.1016/0092-8674(90)90189-L
  45. Edelman, G.M. and K.L. Crossin, Cell adhesion molecules: implications for a molecular histology. Annu Rev Biochem, 1991. 60: p. 155-90.
  46. Yan, C. and P.J. Higgins, Drugging the undruggable: transcription therapy for cancer. Biochim Biophys Acta, 2013. 1835(1): p. 76-85. https://doi.org/10.1016/j.bbcan.2012.11.002
  47. Bushweller, J.H., Targeting transcription factors in cancer - from undruggable to reality. Nat Rev Cancer, 2019. 19(11): p. 611-624. https://doi.org/10.1038/s41568-019-0196-7
  48. Badis, G., et al., Diversity and complexity in DNA recognition by transcription factors. Science, 2009. 324(5935): p. 1720-3. https://doi.org/10.1126/science.1162327
  49. Kawagoe, H., et al., Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia, 1999. 13(5): p. 687-98. https://doi.org/10.1038/sj.leu.2401387
  50. Zhang, W., et al., Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner. J Biol Chem, 2006. 281(26): p. 18059-68. https://doi.org/10.1074/jbc.M601903200
  51. Zhou, H., et al., Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction. J Med Chem, 2013. 56(3): p. 1113-23. https://doi.org/10.1021/jm301649m
  52. Shi, A., et al., Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood, 2012. 120(23): p. 4461-9. https://doi.org/10.1182/blood-2012-05-429449
  53. Karatas, H., et al., High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction. J Am Chem Soc, 2013. 135(2): p. 669-82. https://doi.org/10.1021/ja308415m
  54. Trop-Steinberg, S. and Y. Azar, Is Myc an Important Biomarker? Myc Expression in Immune Disorders and Cancer. Am J Med Sci, 2018. 355(1): p. 67-75. https://doi.org/10.1016/j.amjms.2017.09.010
  55. Fowler, T., et al., Regulation of MYC expression and differential JQ1 sensitivity in cancer cells. PLoS One, 2014. 9(1): p. e87003. https://doi.org/10.1371/journal.pone.0087003
  56. Mazur, P.K., et al., Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med, 2015. 21(10): p. 1163-71. https://doi.org/10.1038/nm.3952
  57. Desterro, J.M., M.S. Rodriguez, and R.T. Hay, Regulation of transcription factors by protein degradation. Cell Mol Life Sci, 2000. 57(8-9): p. 1207-19. https://doi.org/10.1007/PL00000758
  58. Walf-Vorderwülbecke, V., et al., Targeting acute myeloid leukemia by drug-induced c-MYB degradation. Leukemia, 2018. 32(4): p. 882-889. https://doi.org/10.1038/leu.2017.289
  59. Kerres, N., et al., Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6. Cell Rep, 2017. 20(12): p. 2860-2875. https://doi.org/10.1016/j.celrep.2017.08.081
  60. Ohoka, N., et al., Development of a peptide-based inducer of protein degradation targeting NOTCH1. Bioorg Med Chem Lett, 2017. 27(22): p. 4985-4988. https://doi.org/10.1016/j.bmcl.2017.10.020
  61. Wang, X., et al., New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation. Biochem Pharmacol, 2016. 116: p. 200-9. https://doi.org/10.1016/j.bcp.2016.07.012
  62. Lemos, A., et al., Medicinal Chemistry Strategies to Disrupt the p53-MDM2/MDMX Interaction. Med Res Rev, 2016. 36(5): p. 789-844. https://doi.org/10.1002/med.21397
  63. Nayak, S.K., et al., p53-Mdm2 Interaction Inhibitors as Novel Nongenotoxic Anticancer Agents. Curr Cancer Drug Targets, 2018. 18(8): p. 749-772. https://doi.org/10.2174/1568009618666180102160226
  64. Wang, S., et al., Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges. Cold Spring Harb Perspect Med, 2017. 7(5). https://doi.org/10.1101/cshperspect.a026245
  65. Jiang, Z.Y., et al., Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem, 2014. 57(6): p. 2736-45. https://doi.org/10.1021/jm4015279
  66. Yasuda, D., et al., Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity. Bioorg Med Chem Lett, 2016. 26(24): p. 5956-5959. https://doi.org/10.1016/j.bmcl.2016.10.070
  67. Tanaka, N., Inhibition of transcription by pluramycin and bleomycin. J Antibiot (Tokyo), 1970. 23(11): p. 523-30.
  68. Kasparkova, J., et al., Biophysical studies on the stability of DNA intrastrand cross-links of transplatin. Biophys J, 2008. 95(9): p. 4361-71. https://doi.org/10.1529/biophysj.108.136382
  69. Chiang, S.Y., et al., Effects of minor groove binding drugs on the interaction of TATA box binding protein and TFIIA with DNA. Biochemistry, 1994. 33(23): p. 7033-40. https://doi.org/10.1021/bi00189a009
  70. Minuzzo, M., et al., Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci U S A, 2000. 97(12): p. 6780-4. https://doi.org/10.1073/pnas.110154297
  71. Welch, J.J., F.J. Rauscher, 3rd, and T.A. Beerman, Targeting DNA-binding drugs to sequence-specific transcription factor.DNA complexes. Differential effects of intercalating and minor groove binding drugs. J Biol Chem, 1994. 269(49): p. 31051-8.
  72. Melnikova, A.F., et al., Accessibility of the minor groove of DNA in chromatin to the binding of antibiotics netropsin and distamycin A. Mol Biol Rep, 1975. 2(2): p. 135-42.
  73. Wang, S., et al., Minor groove to major groove, an unusual DNA sequence-dependent change in bend directionality by a distamycin dimer. Biochemistry, 2011. 50(35): p. 7674-83. https://doi.org/10.1021/bi200868r
  74. Vorländer, M.K., et al., Molecular mechanism of promoter opening by RNA polymerase III. Nature, 2018. 553(7688): p. 295-300. https://doi.org/10.1038/nature25042
  75. Abascal-Palacios, G., et al., Structural basis of RNA polymerase III transcription initiation. Nature, 2018. 553(7688): p. 301-306. https://doi.org/10.1038/nature25129