PXD018426

PXD018426 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2020-04-08 02:27:18	ID requested
⏵ 1	2021-12-03 09:22:39	announced

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]

submitter keyword: mitochondria, POLRMT, cancer, inhibitor, xenograft, TMT, Fusion, Lumos

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/12/PXD018426

PRIDE project URI

• PRIDE
  1. PXD018426
     1. Label: PRIDE project
     2. Name: Chemical inhibition of mtDNA transcription for treatment of cancer