Transcription of mammalian messenger RNAs by a nuclear RNA polymerase of mitochondrial origin

Abstract

Transcription of eukaryotic genes is performed by three nuclear RNA polymerases, of which RNA polymerase II is thought to be solely responsible for the synthesis of messenger RNAs1. Here we show that transcription of some mRNAs in humans and rodents is mediated by a previously unknown single-polypeptide nuclear RNA polymerase (spRNAP-IV). spRNAP-IV is expressed from an alternative transcript of the mitochondrial RNA polymerase gene (POLRMT). The spRNAP-IV lacks 262 amino-terminal amino acids of mitochondrial RNA polymerase, including the mitochondrial-targeting signal, and localizes to the nucleus. Transcription by spRNAP-IV is resistant to the RNA polymease II inhibitor α-amanitin but is sensitive to short interfering RNA specific for the POLRMT gene. The promoters for spRNAP-IV differ substantially from those used by RNA polymerase II, do not respond to transcriptional enhancers and contain a common functional sequence motif.

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Figure 1: The POLRMT gene is a source of mitochondrial and nuclear protein products.
Figure 2: Two distinct POLRMT -specific polypeptides are encoded by alternative transcripts.
Figure 3: A nuclear protein product of the POLRMT gene participates in the expression of the ZBTB1 , MGC3265 and ALDH12 genes.
Figure 4: Transcription from the ALDH12 and ZBTB1 promoters depends on spRNAP-IV.

References

  1. 1

    Lewin, B. Genes VIII 597–626 (Pearson Prentice Hall, New Jersey, 2004)

    Google Scholar 

  2. 2

    Kurland, C. G. & Andersson, S. G. Origin and evolution of the mitochondrial proteome. Microbiol. Mol. Biol. Rev. 64, 786–820 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Gabaldon, T. & Huynen, M. A. Reconstruction of the proto-mitochondrial metabolism. Science 301, 609 (2003)

    CAS  Article  Google Scholar 

  4. 4

    Masters, B. S., Stohl, L. L. & Clayton, D. A. Yeast mitochondrial RNA polymerase is homologous to those encoded by bacteriophages T3 and T7. Cell 51, 89–99 (1987)

    CAS  Article  Google Scholar 

  5. 5

    Gray, M. W. & Lang, B. F. Transcription in chloroplasts and mitochondria: a tale of two polymerases. Trends Microbiol. 6, 1–3 (1998)

    CAS  Article  Google Scholar 

  6. 6

    Tiranti, V. et al. Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the Expressed Sequence Tags database. Hum. Mol. Genet. 6, 615–625 (1997)

    CAS  Article  Google Scholar 

  7. 7

    Taroni, F. & Rosenberg, L. E. The precursor of the biotin-binding subunit of mammalian propionyl-CoA carboxylase can be translocated into mitochondria as apo- or holoprotein. J. Biol. Chem. 266, 13267–13271 (1991)

    CAS  PubMed  Google Scholar 

  8. 8

    Seidel-Rogol, B. L. & Shadel, G. S. Modulation of mitochondrial transcription in response to mtDNA depletion and repletion in HeLa cells. Nucleic Acids Res. 30, 1929–1934 (2002)

    CAS  Article  Google Scholar 

  9. 9

    King, M. P. & Attardi, G. Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell 52, 811–819 (1988)

    CAS  Article  Google Scholar 

  10. 10

    Smale, S. T. & Kadonaga, J. T. The RNA polymerase II core promoter. Annu. Rev. Biochem. 72, 449–479 (2003)

    CAS  Article  Google Scholar 

  11. 11

    Paule, M. R. & White, R. J. Survey and summary: transcription by RNA polymerases I and III. Nucleic Acids Res. 28, 1283–1298 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Matys, V. et al. TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 31, 374–378 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl Acad. Sci. USA 89, 5547–5551 (1992)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Onodera, Y. et al. Plant nuclear RNA polymerase IV mediates siRNA and DNA methylation-dependent heterochromatin formation. Cell 120, 613–622 (2005)

    CAS  Article  Google Scholar 

  15. 15

    Herr, A. J., Jensen, M. B., Dalmay, T. & Baulcombe, D. C. RNA polymerase IV directs silencing of endogenous DNA. Science 308, 118–120 (2005)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Rantanen, A., Jansson, M., Oldfors, A. & Larsson, N. G. Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis. Mamm. Genome 12, 787–792 (2001)

    CAS  Article  Google Scholar 

  17. 17

    Falkenberg, M. et al. Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. Nature Genet. 31, 289–294 (2002)

    CAS  Article  Google Scholar 

  18. 18

    McCulloch, V. & Shadel, G. S. Human mitochondrial transcription factor B1 interacts with the C-terminal activation region of h-mtTFA and stimulates transcription independently of its RNA methyltransferase activity. Mol. Cell. Biol. 23, 5816–5824 (2003)

    CAS  Article  Google Scholar 

  19. 19

    King, M. P. & Attardi, G. Isolation of human cell lines lacking mitochondrial DNA. Methods Enzymol. 264, 304–313 (1996)

    CAS  Article  Google Scholar 

  20. 20

    Budanov, A. V., Sablina, A. A., Feinstein, E., Koonin, E. V. & Chumakov, P. M. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304, 596–600 (2004)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Pfeifer, A., Ikawa, M., Dayn, Y. & Verma, I. M. Transgenesis by lentiviral vectors: lack of gene silencing in mammalian embryonic stem cells and preimplantation embryos. Proc. Natl Acad. Sci. USA 99, 2140–2145 (2002)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Kaeser, M. D. & Iggo, R. D. Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo. Proc. Natl Acad. Sci. USA 99, 95–100 (2002)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Harlow, E. & Lane, D. Using Antibodies: A Laboratory Manual 276–301; 103–148 (Cold Spring Harbor Laboratory Press, New York, 1999)

    Google Scholar 

  24. 24

    Schuler, G. D., Altschul, S. F. & Lipman, D. J. A workbench for multiple alignment construction and analysis. Proteins 9, 180–190 (1991)

    CAS  Article  Google Scholar 

  25. 25

    Grundy, W. N., Bailey, T. L. & Elkan, C. P. ParaMEME: a parallel implementation and a web interface for a DNA and protein motif discovery tool. Comput. Appl. Biosci. 12, 303–310 (1996)

    CAS  PubMed  Google Scholar 

  26. 26

    Lawrence, C. E. et al. Detecting subtle sequence signals: a Gibbs sampling strategy for multiple alignment. Science 262, 208–214 (1993)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Hertz, G. Z. & Stormo, G. D. Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics 15, 563–577 (1999)

    CAS  Article  Google Scholar 

  28. 28

    Keich, U. & Pevzner, P. A. Subtle motifs: defining the limits of motif finding algorithms. Bioinformatics 18, 1382–1390 (2002)

    CAS  Article  Google Scholar 

  29. 29

    Kel, A. E. et al. MATCH: A tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res. 31, 3576–3579 (2003)

    CAS  Article  Google Scholar 

  30. 30

    Kent, W. J. BLAT–the BLAST-like alignment tool. Genome Res. 12, 656–664 (2002)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The work was supported by funds provided by The Lerner Research Institute to P.M.C. and by NIH and RFBR to P.M.C.

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Correspondence to Peter M. Chumakov.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

Supplementary Figures S1-S10 with legends and additional references. (PDF 1417 kb)

Supplementary Notes

Contains Supplementary Methods, Supplementary Table and information on microarray experiment design in MIAME-copliant format. (PDF 68 kb)

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Kravchenko, J., Rogozin, I., Koonin, E. et al. Transcription of mammalian messenger RNAs by a nuclear RNA polymerase of mitochondrial origin. Nature 436, 735–739 (2005). https://doi.org/10.1038/nature03848

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