PXD048833-1

PXD048833 is an original dataset announced via ProteomeXchange.

Title	Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage
Description	Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induced chromosome mis-segregation in non-transformed RPE1-hTERT cells and derived multiple stable clones with various degrees of aneuploidy. We performed an unbiased genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogated their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activated the DNA damage response, and were consequently more resistant to further DNA damage induction. Aneuploid cells also exhibited elevated RAF/MEK/ERK pathway activity, and were more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitized aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. These results were validated in human cancer cell lines. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, revealing a novel therapeutically-relevant cellular dependency of aneuploid cells. This submission contains the raw files, the library used for the analysis, and the corresponding DIA-NN report and associated files.
HostingRepository	PRIDE
AnnounceDate	2024-07-08
AnnouncementXML	Submission_2024-07-08_03:39:32.208.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Anja Freiwald
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-24 04:02:21	ID requested
⏵ 1	2024-07-08 03:39:32	announced

Dataset with its publication pending

submitter keyword: cancer, DNA damage,quantitative proteomics, aneuploidy

Markus Ralser
contact affiliation	Charité Universitätsmedizin, Department of Biochemistry, 10117 Berlin, Germany The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK Max Planck Institute for Molecular Genetics, Berlin, Germany
contact email	Markus.ralser@charite.de
lab head
Anja Freiwald
contact affiliation	Charité
contact email	anja.freiwald@charite.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048833
     1. Label: PRIDE project
     2. Name: Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage