PXD023435

PXD023435 is an original dataset announced via ProteomeXchange.

Title	CDK4/6 inhibitors induce repication stress to cause long-term cell cycle withdrawal
Description	CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are licenced to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a temporary cell cycle arrest in G1 causes long-lasting effects on tumour growth. Here we demonstrate that a prolonged G1-arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. This causes a failure in DNA replication after release from that arrest, resulting in a p53-dependent withdrawal from the cell cycle. If p53 is absent, then cells bypass the G2-checkpoint and undergo a catastrophic mitosis resulting in excessive DNA damage. These data therefore link CDK4/6 inhibition to genotoxic stress; a phenotype that is shared by most other broad-spectrum anti-cancer drugs. This provides a rationale to predict responsive tumour types and effective combination therapies, as demonstrated by the fact that chemotherapeutics that cause replication stress also induce sensitivity to CDK4/6 inhibition.
HostingRepository	PRIDE
AnnounceDate	2021-12-20
AnnouncementXML	Submission_2021-12-20_08:23:18.264.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tony Ly
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-06 02:44:05	ID requested
⏵ 1	2021-12-20 08:23:18	announced

Dataset with its publication pending

submitter keyword: CDK4/6 cancer replication stress cell cycle senescence

Tony Ly
contact affiliation	Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
contact email	tly@ed.ac.uk
lab head
Tony Ly
contact affiliation	University of Edinburgh
contact email	tly@ed.ac.uk
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/PXD023435

PRIDE project URI

• PRIDE
  1. PXD023435
     1. Label: PRIDE project
     2. Name: CDK4/6 inhibitors induce repication stress to cause long-term cell cycle withdrawal