PXD017978

PXD017978 is an original dataset announced via ProteomeXchange.

Title	Gain-of-function mutations amplify cytotoxic FAM111 protease activity in poikiloderma, gracile bone dysplasia and Kenny-Caffey syndromes
Description	Dominant missense mutations in the human serine protease FAM111A underlie perinatally lethal gracile bone dysplasia and Kenny-Caffey syndrome 1-3, yet how FAM111A mutations lead to disease is not known. We show that FAM111A proteolytic activity suppresses DNA replication and transcription by displacing key effectors of these processes from chromatin, triggering rapid programmed cell death by Caspase-dependent apoptosis to potently undermine cell viability. Patient-associated point mutations in FAM111A exacerbate these phenotypes by hyperactivating its intrinsic protease activity. Moreover, FAM111A forms a complex with the uncharacterized homologous serine protease FAM111B, point mutations in which cause a hereditary fibrosing poikiloderma syndrome 4, and we demonstrate that disease-associated FAM111B mutants display amplified proteolytic activity and phenocopy the cellular impact of deregulated FAM111A catalytic activity. Thus, patient-associated FAM111A and FAM111B mutations may drive multisystem disorders via a common gain-of-function mechanism that relieves inhibitory constraints on their protease activities to powerfully undermine cellular fitness.
HostingRepository	PRIDE
AnnounceDate	2020-08-10
AnnouncementXML	Submission_2020-08-10_01:03:24.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Fabian Coscia
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-10 09:20:09	ID requested
⏵ 1	2020-08-10 01:03:24	announced

Dataset with its publication pending

submitter keyword: FAM111, Kenny-Caffey syndromes, replication stress, transcrition, genetic disorder, Kenny-Caffey syndromes, poikiloderma, proteases

Niels Mailand
contact affiliation	University of Copenhagen Novo Nordisk Foundation Center for Protein Research Blegdamsvej 3B 2200 Copenhagen N Denmark
contact email	niels.mailand@cpr.ku.dk
lab head
Fabian Coscia
contact affiliation	University of Copenhagen NNF Center for Protein Research
contact email	fabian.coscia@cpr.ku.dk
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/2020/08/PXD017978

PRIDE project URI

• PRIDE
  1. PXD017978
     1. Label: PRIDE project
     2. Name: Gain-of-function mutations amplify cytotoxic FAM111 protease activity in poikiloderma, gracile bone dysplasia and Kenny-Caffey syndromes