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  Small-molecule inhibitors of human mitochondrial DNA transcription

Bonekamp, N. A., Peter, B., Hillen, H. S., Felser, A., Bergbrede, T., Choidas, A., et al. (2020). Small-molecule inhibitors of human mitochondrial DNA transcription. Nature, 588(7839), 712-716. doi:10.1038/s41586-020-03048-z.

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 Creators:
Bonekamp, N. A., Author
Peter, B., Author
Hillen, H. S.1, Author              
Felser, A., Author
Bergbrede, T., Author
Choidas, A., Author
Horn, M., Author
Unger, A., Author
Di Lucrezia, R. , Author
Atanassov, I., Author
Li, X., Author
Koch, U., Author
Menninger, S., Author
Boros, J., Author
Habenberger, P., Author
Giavalisco, P., Author
Cramer, P.2, Author              
Denzel, M. S., Author
Nussbaumer, P., Author
Klebl, B., Author
Falkenberg, M., AuthorGustafsson, C. M., AuthorLarsson, N.-G., Author more..
Affiliations:
1Research Group Structure and Function of Molecular Machines, MPI for Biophysical Chemistry, Max Planck Society, ou_3265856              
2Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              

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Free keywords: Cancer therapy; Mitochondria; Transcription
 Abstract: Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system1,2,3,4,5,6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7,8,9,10,11,12,13,14,15,16,17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.

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Language(s): eng - English
 Dates: 2020-12-162020-12-24
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41586-020-03048-z
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Title: Nature
Source Genre: Journal
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Pages: - Volume / Issue: 588 (7839) Sequence Number: - Start / End Page: 712 - 716 Identifier: -