PXD026481

PXD026481 is an original dataset announced via ProteomeXchange.

Title	Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen
Description	Cancer cells depend on mitochondria to sustain their increased metabolic needs therefore, mitochondria constitute an interesting target for cancer treatment. We recently developed novel small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively target mitochondrial gene expression. IMTs showed potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms involved in resistance to IMTs. We employed a CRISPR-Cas9 whole genome screen to determine pathways responsible for resistance to acute IMT1 treatment. Loss of genes belonging to VHL and mTORC1 pathways caused IMT1 resistance. The relevance of these pathways was then validated by chemical modulation of these processes in cancer cells. We also generated IMT1-resistant cells to dissect responses to chronic mitochondrial gene expression impairment. We report that acquired resistance to IMT1 occurs through compensatory increase of mtDNA levels, transcripts and proteins. We found that chloramphenicol-mediated inhibition of mitochondrial translation impaired resistant cells’ survival. The identified susceptibility and resistance mechanisms to IMTs are important for future pharmacological interventions with mitochondria-targeted therapies.
HostingRepository	PRIDE
AnnounceDate	2021-11-11
AnnouncementXML	Submission_2021-11-11_08:02:13.130.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Oleksandr Lytovchenko
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-04 02:52:21	ID requested
⏵ 1	2021-11-11 08:02:13	announced

Dataset with its publication pending

submitter keyword: inhibitor of mitochondrial transcription, CRISPR-Cas9 genetic screen, chemoresistance, cancer, mtDNA

Nils-Göran Larsson
contact affiliation	Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm 17177, Sweden
contact email	nils-goran.larsson@ki.se
lab head
Oleksandr Lytovchenko
contact affiliation	Karolinska Institutet
contact email	lytovchenko@gmail.com
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/2021/11/PXD026481

PRIDE project URI

• PRIDE
  1. PXD026481
     1. Label: PRIDE project
     2. Name: Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen