Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Transcription by RNA polymerase III: more complex than we thought


RNA polymerase (Pol) III is highly specialized for the production of short non-coding RNAs. Once considered to be under relatively simple controls, recent studies using chromatin immunoprecipitation followed by sequencing (ChIP–seq) have revealed unexpected levels of complexity for Pol III regulation, including substantial cell-type selectivity and intriguing overlap with Pol II transcription. Here I describe these novel insights and consider their implications and the questions that remain.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Basal transcription machinery and promoter structure at RNA polymerase III-transcribed genes.
Figure 2: Schematic comparison of features distinguishing many active and inactive tRNA genes.
Figure 3: How specific histone modifications correlate with expression of RNA polymerase III- and RNA polymerase II-transcribed genes.

Similar content being viewed by others


  1. Roeder, R. G. & Rutter, W. J. Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms. Nature 224, 234–237 (1969).

    Article  CAS  Google Scholar 

  2. Marshall, L. & White, R. J. Non-coding RNA production by RNA polymerase III is implicated in cancer. Nature Rev. Cancer 8, 911–914 (2008).

    Article  CAS  Google Scholar 

  3. Marshall, L., Kenneth, N. S. & White, R. J. Elevated tRNAiMet synthesis can drive cell proliferation and oncogenic transformation. Cell 133, 78–89 (2008).

    Article  CAS  Google Scholar 

  4. Kedinger, C., Gniazdowski, M., Mandel, J. L., Gissinger, F. & Chambon, P. α-Amanitin: a specific inhibitor of one of two DNA-dependent RNA polymerase activities from calf thymus. Biochem. Biophys. Res. Commun. 38, 165–171 (1970).

    Article  CAS  Google Scholar 

  5. Harismendy, O. et al. Genome-wide location of yeast RNA polymerase III transcription machinery. EMBO J. 22, 4738–4747 (2003).

    Article  CAS  Google Scholar 

  6. Roberts, D. N., Stewart, A. J., Huff, J. T. & Cairns, B. R. The RNA polymerase III transcriptome revealed by genome-wide localization and activity-occupancy relationships. Proc. Natl Acad. Sci. USA 100, 14695–14700 (2003).

    Article  CAS  Google Scholar 

  7. Moqtaderi, Z. & Struhl, K. Genome-wide occupancy profile of the RNA polymerase III machinery in Saccharomyces cerevisiae reveals loci with incomplete transcription complexes. Mol. Cell. Biol. 24, 4118–4127 (2004).

    Article  CAS  Google Scholar 

  8. Barski, A. et al. Pol II and its associated epigenetic marks are present at Pol III-transcribed noncoding RNA genes. Nature Struct. Mol. Biol. 17, 629–634 (2010).

    Article  CAS  Google Scholar 

  9. Canella, D., Praz, V., Reina, J. H., Cousin, P. & Hernandez, N. Defining the RNA polymerase III transcriptome: genome-wide localization of the RNA polymerase III transcription machinery in human cells. Genome Res. 20, 710–721 (2010).

    Article  CAS  Google Scholar 

  10. Moqtaderi, Z. et al. Genomic binding profiles of functionally distinct RNA polymerase III transcription complexes in human cells. Nature Struct. Mol. Biol. 17, 635–640 (2010).

    Article  CAS  Google Scholar 

  11. Oler, A. J. et al. Human RNA polymerase III transcriptomes and relationships to Pol II promoter chromatin and enhancer-binding factors. Nature Struct. Mol. Biol. 17, 620–628 (2010).

    Article  CAS  Google Scholar 

  12. Raha, D. et al. Close association of RNA polymerase II and many transcription factors with Pol III genes. Proc. Natl Acad. Sci. USA 107, 3639–3644 (2010).

    Article  CAS  Google Scholar 

  13. Batzer, M. A. & Deininger, P. L. Alu repeats and human genomic diversity. Nature Rev. Genet. 3, 370–379 (2002).

    Article  CAS  Google Scholar 

  14. Noma, K., Cam, H. P., Maraia, R. & Grewal, S. I. A role for TFIIIC transcription factor complex in genome organization. Cell 125, 859–872 (2006).

    Article  CAS  Google Scholar 

  15. Borchert, G. M., Lanier, W. & Davidson, B. L. RNA polymerase III transcribes human microRNAs. Nature Struct. Mol. Biol. 13, 1097–1101 (2006).

    Article  CAS  Google Scholar 

  16. Ozsolak, F. et al. Chromatin structure analyses identify miRNA promoters. Genes Dev. 22, 3172–3183 (2008).

    Article  CAS  Google Scholar 

  17. Bortolin-Cavaille, M., Dance, M., Weber, M. & Cavaille, J. C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts. Nucleic Acids Res. 37, 3464–3473 (2009).

    Article  CAS  Google Scholar 

  18. Schramm, L. & Hernandez, N. Recruitment of RNA polymerase III to its target promoters. Genes Dev. 16, 2593–2620 (2002).

    Article  CAS  Google Scholar 

  19. Schramm, L., Pendergrast, P. S., Sun, Y. & Hernandez, N. Different human TFIIIB activities direct RNA polymerase III transcription from TATA-containing and TATA-less promoters. Genes Dev. 14, 2650–2663 (2000).

    Article  CAS  Google Scholar 

  20. Dittmar, K. A., Goodenbour, J. M. & Pan, T. Tissue-specific differences in human transfer RNA expression. PLoS Genet. 2, 2107–2115 (2006).

    Article  CAS  Google Scholar 

  21. White, R. J. RNA polymerases I and III, growth control and cancer. Nature Rev. Mol. Cell Biol. 6, 69–78 (2005).

    Article  CAS  Google Scholar 

  22. Ciesla, M. & Boguta, M. Regulation of RNA polymerase III transcription by Maf1 protein. Acta Biochim. Pol. 55, 215–225 (2008).

    CAS  PubMed  Google Scholar 

  23. Sutcliffe, J. E., Brown, T. R. P., Allison, S. J., Scott, P. H. & White, R. J. Retinoblastoma protein disrupts interactions required for RNA polymerase III transcription. Mol. Cell. Biol. 20, 9192–9202 (2000).

    Article  CAS  Google Scholar 

  24. Crighton, D. et al. p53 represses RNA polymerase III transcription by targeting TBP and inhibiting promoter occupancy by TFIIIB. EMBO J. 22, 2810–2820 (2003).

    Article  CAS  Google Scholar 

  25. Desai, N. et al. Two steps in Maf1-dependent repression of transcription by RNA polymerase III. J. Biol. Chem. 280, 6455–6462 (2005).

    Article  CAS  Google Scholar 

  26. Kenneth, N. S. et al. TRRAP and GCN5 are used by c-Myc to activate RNA polymerase III transcription. Proc. Natl Acad. Sci. USA 104, 14917–14922 (2007).

    Article  CAS  Google Scholar 

  27. Gomez-Roman, N., Grandori, C., Eisenman, R. N. & White, R. J. Direct activation of RNA polymerase III transcription by c-Myc. Nature 421, 290–294 (2003).

    Article  CAS  Google Scholar 

  28. Owen, T. J. et al. Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors. Mol. Cancer 9, 241 (2010).

    Article  Google Scholar 

  29. Kenneth, N. S. & White, R. J. Regulation by c-Myc of ncRNA expression. Curr. Opin. Genet. Dev. 19, 38–43 (2009).

    Article  CAS  Google Scholar 

  30. Steiger, D., Furrer, M., Schwinkendorf, D. & Gallant, P. Max-independent functions of Myc in Drosophila melanogaster. Nature Genet. 40, 1084–1091 (2008).

    Article  CAS  Google Scholar 

  31. Johnson, S. A. S., Dubeau, L. & Johnson, D. L. Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation. J. Biol. Chem. 283, 19184–19191 (2008).

    Article  CAS  Google Scholar 

  32. Listerman, I., Bledau, A. S., Grishina, I. & Neugebauer, K. M. Extragenic accumulation of RNA polymerase II enhances transcription by RNA polymerase III. PLoS Genet. 3, e212 (2007).

    Article  Google Scholar 

  33. Haldar, D. & Kamakaka, R. T. tRNA genes as chromatin barriers. Nature Struct. Mol. Biol. 13, 192–193 (2006).

    Article  CAS  Google Scholar 

  34. Mertens, C. & Roeder, R. G. Different functional modes of p300 in activation of RNA polymerase III transcription from chromatin templates. Mol. Cell. Biol. 28, 5764–5776 (2008).

    Article  CAS  Google Scholar 

  35. Boyer, L. A., Latek, R. R. & Peterson, C. L. The SANT domain: a unique histone-tail-binding module? Nature Rev. Mol. Cell Biol. 5, 158–163 (2004).

    Article  CAS  Google Scholar 

  36. Donze, D. & Kamakaka, R. T. RNA polymerase III and RNA polymerase II promoter complexes are heterochromatin barriers in Saccharomyces cerevisiae. EMBO J. 20, 281–287 (2001).

    Google Scholar 

  37. Oki, M. & Kamakaka, R. T. Barrier function at HMR. Mol. Cell 19, 707–716 (2005).

    Article  CAS  Google Scholar 

  38. Scott, K. C., Merrett, S. L. & Willard, H. F. A heterochromatin barrier partitions the fission yeast centromere into discrete chromatin domains. Curr. Biol. 16, 119–129 (2006).

    Article  CAS  Google Scholar 

  39. Lunyak, V. V. et al. Developmentally regulated activation of a SINE B2 repeat as a domain boundary in organogenesis. Science 317, 248–251 (2007).

    Article  CAS  Google Scholar 

  40. Roman, A. C. et al. Dioxin receptor and slug transcription factors regulate the insulator activity of B1 SINE retrotransposons via an RNA polymerase switch. Genome Res. 21, 422–432 (2011).

    Article  CAS  Google Scholar 

Download references


The author gratefully acknowledges funding from Cancer Research UK.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Robert J. White.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links


Author's homepage



(5S ribosomal RNA). The smallest of the rRNAs. It is found in the large subunit of ribosomes.


Binds and represses P-TEFb, a factor that stimulates transcript elongation by RNA polymerase II.


Acts as a scaffold within the signal recognition particle (SRP), which inserts nascent polypeptides into membranes.


The RNA component of RNase P, which processes the 5′ end of tRNAs.


Human Y RNA, which has putative roles in DNA replication and quality control of non-coding RNAs.


Mitochondrial RNA processing (MRP) RNA is part of a ribonucleoprotein particle that processes precursor ribosomal RNA and mitochondrial DNA replication primers. MRP RNA (encoded by the RMRP gene) also associates with the catalytic subunit of human telomerase reverse transcriptase (TERT) to form an RNA-dependent RNA polymerase which generates RNAs that are processed by DICER into small interfering RNAs.

SANT domain

A motif of ~50 amino acid residues that is found in transcription cofactors, chromatin-remodelling proteins and BDP1.

U6 snRNA

(U6 small nuclear RNA). A component of splicesomes, which are required for splicing precursor mRNAs.

Vault RNA

Part of a very large ribonucleoprotein particle that is implicated in multidrug resistance and intracellular transport. Although 20% of vault RNA is found in vault particles, ~80% is free in the cytosol, where it is processed by DICER to generate small intefering RNAs that downregulate CYP3A4, a key enzyme in drug metabolism.

Rights and permissions

Reprints and permissions

About this article

Cite this article

White, R. Transcription by RNA polymerase III: more complex than we thought. Nat Rev Genet 12, 459–463 (2011).

Download citation

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing