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Structural basis of mitochondrial transcription

Nature Structural & Molecular Biology volume 25, pages 754–765 (2018)Cite this article

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Abstract

The mitochondrial genome is transcribed by a single-subunit DNA-dependent RNA polymerase (mtRNAP) and its auxiliary factors. Structural studies have elucidated how mtRNAP cooperates with its dedicated transcription factors to direct RNA synthesis: initiation factors TFAM and TFB2M assist in promoter-DNA binding and opening by mtRNAP while the elongation factor TEFM increases polymerase processivity to the levels required for synthesis of long polycistronic mtRNA transcripts. Here, we review the emerging body of structural and functional studies of human mitochondrial transcription, provide a molecular movie that can be used for teaching purposes and discuss the open questions to guide future directions of investigation.

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Fig. 1: Structure of mitochondrial RNA polymerase (mtRNAP).
Fig. 2: Structure of transcribing mtRNAP (elongation complex).
Fig. 3: Structures of initiation factors TFAM and TFB2M.
Fig. 4: Structure of the mitochondrial transcription initiation complex.
Fig. 5: Structure of elongation factor TEFM and the processive antitermination complex.
Fig. 6: Structure of MTERF1.
Fig. 7: A structural view of the human mitochondrial transcription cycle.

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Acknowledgements

We wish to thank current and past members of the laboratories of P.C. and D.T. for critical discussions and valuable comments. H.S.H. was supported by a Boehringer Ingelheim Fonds PhD fellowship. P.C. was supported by the Deutsche Forschungsgemeinschaft (SFB860 and SPP1935), the European Research Council Advanced Investigator Grant TRANSREGULON (grant agreement 693023) and the Volkswagen Foundation. D.T. was supported by NIH RO1 GM104231 and R01 GM118941.

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  1. Dmitry Temiakov

    Present address: Department of Biochemistry & Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Authors and Affiliations

  1. Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany

    Hauke S. Hillen & Patrick Cramer

  2. Department of Cell Biology, Rowan University, School of Osteopathic Medicine, Stratford, NJ, USA

    Dmitry Temiakov

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H.S.H. prepared figures and Supplementary Video 1. H.S.H., D.T. and P.C. wrote the manuscript.

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Correspondence to Hauke S. Hillen or Patrick Cramer.

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Supplementary information

Supplementary Video 1

Structural basis of human mitochondrial transcription. A movie depicting events in the human mitochondrial transcription cycle based on known molecular structures. To initiate transcription, the mitochondrial RNA polymerase (PDB ID: 3SPA) is recruited to the promoter by TFAM (PDB ID: 3TMM and 3TQ6) via the tether helix in the mtRNAP N-terminal extension, to form the closed pre-initiation complex. Binding of TFB2M (PDB ID: 6ERO) then induces open initiation complex formation (PDB ID: 6ERP). Note that formation of the pre-initiation complex is not depicted due to a lack of structural information for this transient complex. During transition to elongation phase, the initiation factors are lost and the upstream DNA undergoes re-arrangement to occupy the site on mtRNAP previously bound by TFB2M, forming the elongation complex (PDB ID: 4BOC). Faithful transcription of long, polycistronic mitochondrial transcripts requires elongation factor TEFM, whose binding (only the active C-terminal domain is shown: PDB ID: 5OL8) results in formation of a processive anti-termination complex (PDB ID: 5OLA). Transcription termination is not shown due to lack of structural data on the interaction between mtRNAP and termination factor(s).

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Hillen, H.S., Temiakov, D. & Cramer, P. Structural basis of mitochondrial transcription. Nat Struct Mol Biol 25, 754–765 (2018). https://doi.org/10.1038/s41594-018-0122-9

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