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Dysregulation of the basal RNA polymerase transcription apparatus in cancer

Nature Reviews Cancer volume 13, pages 299–314 (2013)Cite this article

Subjects

Key Points

  • The core RNA polymerase (Pol) subunits and general transcription factors (GTFs) are rarely mutated in cancer, although some GTFs are consistently overexpressed in tumours and this is thought to contribute to malignancy in some cases.

  • Subunits of the mediator complex are increasingly being found to be mutated or amplified in tumours, where they have oncogenic or tumour suppressive activities and functions, depending on the genetic background and cellular context.

  • Regulators of post-initiation stages of transcription, particularly components of RNA Pol II super elongation complexes (SECs), are recurrently mutated in cancer, particularly haematological malignancies through translocation with the mixed lineage leukaemia (MLL) family of transcription factors. The resultant fusion proteins facilitate the enhanced transcription elongation of homeobox (HOX) transcription factors that are involved in embryonic development and haematopoietic cell differentiation, which drives malignancy.

  • RNA Pol I and RNA Pol III are consistently dysregulated in cancer, which is mostly mediated through upstream oncogenic and tumour suppressive signalling pathways rather than through mutations.

  • The most potent and pervasive oncogenic and tumour suppressive components of the transcription apparatus seem to be those that are capable of modulating all three RNA Pols.

  • RNA Pol I transcriptional overactivity has been shown to be necessary for the survival of haematological tumour cells, and the RNA Pol I GTF SL-1 has been successfully targeted using a small-molecule inhibitor to therapeutically treat transgenic mouse models of cancer in vivo. RNA Pol I transcription therapy is currently entering Phase I trials in humans for the treatment of lymphoma and leukaemia.

  • Components of the core transcription apparatus, including the mediator complex and the SEC, represent bone fide therapeutic targets for cancer treatment not only as advanced broad-spectrum cytotoxics but also potentially as part of the new paradigm of personalized medicine.

Abstract

Mutations that directly affect transcription by RNA polymerases rank among the most central mediators of malignant transformation, but the frequency of new anticancer drugs that selectively target defective transcription apparatus entering the clinic has been limited. This is because targeting the large protein–protein and protein–DNA interfaces that control both generic and selective aspects of RNA polymerase transcription has proved extremely difficult. However, recent technological advances have led to a 'quantum leap' in our comprehension of the structure and function of the core RNA polymerase components, how they are dysregulated in a broad range of cancers and how they may be targeted for 'transcription therapy'.

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Figure 1: Basal transcription machineries and promoter structures of the eukaryotic DNA-dependent RNA polymerases I, II and III.
Figure 2: Activation of RNA polymerase II transcription and its druggable interfaces.

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Acknowledgements

Owing to scope and space limitations the authors have not been able to individually cite many of the original publications that have contributed substantially to the field. The authors sincerely apologize to the authors of these publications. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia programme and project grants; Leukemia Foundation Grant in Aid; Prostate Cancer Foundation of Australia grant in aid; NHMRC Research Fellowship to R.D.H. and R.B.P.; NHMRC Postgraduate Research Scholarship, GSK Postgraduate Research Scholarship and Leukemia Foundation Postdoctoral Fellowship to M.J.B.; Cancer Council of Victoria Sir Edward Weary Dunlop Clinical Research Fellowship and NHMRC Clinical Research Fellowship to G.A.M.

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Authors and Affiliations

  1. Division of Cancer Research, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, 8006, Victoria, Australia

    Megan J. Bywater, Richard B. Pearson, Grant A. McArthur & Ross D. Hannan

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Victoria, Australia

    Megan J. Bywater, Richard B. Pearson & Ross D. Hannan

  3. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Richard B. Pearson, Grant A. McArthur & Ross D. Hannan

  4. Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia

    Richard B. Pearson & Ross D. Hannan

  5. Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia

    Grant A. McArthur

  6. Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, Melbourne, 8006, Victoria, Australia

    Grant A. McArthur

  7. School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Queensland, Australia

    Ross D. Hannan

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Glossary

Mediator complex

A multiprotein complex that functions as an RNA Pol II transcriptional co-activator in all eukaryotes, although it is unable to bind specific DNA sequences, it functions as an adaptor between sequence-specific transcription factors bound at regulatory elements, and RNA Pol II and GTFs.

General transcription factors

(GTFs). Also known as basal transcriptional factors. A class of protein transcription factors that bind to specific sites on DNA to activate transcription and are essential for basal (as opposed to activated) RNA Pol I, RNA Pol II and RNA Pol III transcription.

TATA box

A DNA sequence (cis-regulatory element) that is found in the core promoter region of a subset of RNA Pol II and RNA Pol III genes. For RNA Pol II the TATA box is involved in recruiting the RNA Pol II general transcription factor (GTF) transcription initiation factor IID (TFIID) that contains TATA-box-binding protein (TBP).

SL-1

An essential transcription initiation factor complex unique to RNA Pol I consisting of TATA-box-binding protein (TBP) and at least five TBP-associated factors (TAFs) that functions to recruit RNA Pol I to the ribosomal RNA gene promoters.

Nucleotide excision repair

A DNA repair mechanism that removes mutations resulting from ultraviolet-induced DNA damage.

Xeroderma pigmentosum

An autosomal recessive genetic disorder of nucleotide excision repair caused by mutations in at least eight separate genes including XPC, ERCC2 and POLH, in which the ability to repair DNA damage caused by ultraviolet light is deficient.

Pre-initiation complex

(PIC). The complex of proteins that is necessary for the initiation of RNA Pol I, RNA Pol II and RNA Pol III transcription in eukaryotes where it helps position RNA Pol over gene transcription start sites, denatures the DNA, and positions the DNA in the RNA Pol active site for transcription.

Capping

The process in which a guanine nucleotide is connected to the 5′ end of newly RNA Pol II transcribed mRNA via an unusual 5′ to 5′ triphosphate linkage that facilitates nuclear export of the mRNA, prevents its degradation by exonucleases, and promotes translation and 5′ proximal intron excision.

Pausing

A control step in gene transcription by which RNA Pol II pauses ∼20–40 nucleotides downstream of the transcription start site and requires specific stimuli and elongation factors to overcome the pausing block to enter productive elongation.

C-terminal domain

(CTD). The extended CTD of RPB1 that is phosphorylated at Ser2 and Ser5 in the 52 heptad repeat sequence, YSPTSPS, which is crucial for promoter escape and elongation.

Super elongation complex

(SEC). Consists of the RNA Pol II elongation factors including ELL proteins, positive transcription elongation factor (P-TEFb) and several mixed lineage leukaemia (MLL) translocation partners and is required for rapid transcriptional induction in the presence or absence of paused RNA Pol II.

Homeobox (HOX) genes

A highly conserved family of homeodomain-containing transcription factors involved in the control of early development, including haematopoiesis, the dysregulation of which is associated with a number of haematological malignancies.

DNA-alkylating agents

The oldest class of anticancer drugs still commonly used for cancer treatment that function as methylating agents that form adducts at the O and N atoms in DNA.

Nucleotide analogues

Among the first chemotherapeutic agents to be introduced for the medical treatment of cancer, they include a variety of purine and pyrimidine nucleotide derivatives that function as antimetabolites and compete with physiological nucleotides to induce cytotoxicity.

Anthracyclines

A class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var. caesius, which function by intercalating between base pairs of the DNA–RNA strand, thus preventing DNA and RNA synthesis; they also inhibit topoisomerase II, which leads to DNA breaks.

DNA crosslinks

DNA crosslinks (either intrastrand or interstrand) block DNA replication and/or DNA transcription and occur when various exogenous or endogenous agents react with two different positions in the DNA to form covalent adducts with DNA bases.

Platinum compounds

A class of platinum-containing anticancer drugs (for example, cisplatin) that function by crosslinking DNA.

Peptide nucleic acids

(PNAs). Nucleic acid analogues in which the sugar–phosphate backbone of natural nucleic acids has been replaced by a synthetic peptide backbone, resulting in an achiral and uncharged mimic that is capable of sequence-specific recognition of DNA and RNA.

Transcription activator-like effectors

(TALEs). A class of naturally occurring DNA-binding proteins found in the plant pathogen Xanthomonas spp. in which the DNA-binding domain of each TALE consists of tandem 34-amino acid repeat modules that can be rearranged according to a simple cipher to target new DNA sequences for the use in a wide variety of genome-engineering applications, including transcriptional modulation.

Micro-focus beam lines

To obtain structures from increasingly small crystals (<20 micrometers), synchrotron facilities have developed micro-focus beam lines or high-intensity beams with a small focal spot. The demand to use even smaller crystals, (<10 micrometers), has necessitated the development of a 'mini-beam' apparatus.

Third-generation synchrotron radiation sources

Third-generation radiation sources, either low energy (1–2 GeV) or high energy (6–8 GeV), use novel insertion devices in synchrotron storage rings to enhance the intensity of the radiation source, thus providing two or more orders of magnitude higher brightness than earlier generation sources.

Free electron lasers

Produce ultra-intense, ultra-short X-ray pulses that have applications in exploring new frontiers in science research such as studying atoms in motion, chemical reactions and phase transitions in materials with atomic resolution on the femtosecond timescale.

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Bywater, M., Pearson, R., McArthur, G. et al. Dysregulation of the basal RNA polymerase transcription apparatus in cancer. Nat Rev Cancer 13, 299–314 (2013). https://doi.org/10.1038/nrc3496

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