PXD018426 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Chemical inhibition of mtDNA transcription for treatment of cancer |
Description | Mitochondrial oxidative phosphorylation (OXPHOS) is important for cancer cell growth and the persistence of therapy-resistant cancer stem cells. Here, we have developed novel first-in-class inhibitors of mitochondrial transcription (IMTs) targeting mtDNA gene expression. We show that IMTs specifically target mitochondrial RNA polymerase (POLRMT) and we defined the IMT binding site using exome sequencing of cells rendered resistant to IMTs by chemical mutagenesis and cryo-EM. IMTs act as allosteric inhibitors of POLRMT, impairing binding of the DNA-RNA hybrid and translocation of the nascent RNA. IMT treatment impairs OXPHOS in a dose-dependent way and decreases cell viability in various tumour cells. Surprisingly, several weeks of per oral IMT treatment is well tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in human cancer xenografts. We thus show that the IMTs represent a novel promising class of drugs for tumour treatment acting by inhibition of mtDNA gene expression. |
HostingRepository | PRIDE |
AnnounceDate | 2021-12-03 |
AnnouncementXML | Submission_2021-12-03_09:22:38.902.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Ilian Atanassov |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion Lumos; Orbitrap Fusion |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-04-08 02:27:18 | ID requested | |
⏵ 1 | 2021-12-03 09:22:39 | announced | |
Publication List
Bonekamp NA, Peter B, Hillen HS, Felser A, Bergbrede T, Choidas A, Horn M, Unger A, Di Lucrezia R, Atanassov I, Li X, Koch U, Menninger S, Boros J, Habenberger P, Giavalisco P, Cramer P, Denzel MS, Nussbaumer P, Klebl B, Falkenberg M, Gustafsson CM, Larsson NG, Small-molecule inhibitors of human mitochondrial DNA transcription. Nature, 588(7839):712-716(2020) [pubmed] |
Keyword List
submitter keyword: mitochondria, POLRMT, cancer, inhibitor, xenograft, TMT, Fusion, Lumos |
Contact List
Nils-Göran Larsson |
contact affiliation | Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, D-50931, Germany Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SE-17177, Sweden Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, 171 77 Stockholm, Sweden |
contact email | nils-goran.larsson@ki.se |
lab head | |
Ilian Atanassov |
contact affiliation | Max Planck Institute for Biology of Aging |
contact email | Ilian.Atanassov@age.mpg.de |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD018426
- Label: PRIDE project
- Name: Chemical inhibition of mtDNA transcription for treatment of cancer