PXD027035

PXD027035 is an original dataset announced via ProteomeXchange.

Title	Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death
Description	Regulation of RNA processing contributes profoundly to tissue development and physiology. The serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA–DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Accumulation of lipids in SRSF1-deficient hepatocytes is quickly followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. This pathogenesis is recapitulated in SRSF1-depleted human liver cancer cells illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. This data set contains a proteomic comparison of hepatocytes from wild type vs. acute knockout of SRSF1. The acute knockout was generated by injecting 8-week-old SRSF1 fl/fl mice with a viral vector expressing Cre under the control of the liver-specific thyroxine binding globulin (TBG) promoter (AAV8-TBG-iCre). Controls were generated by injecting AAV8-TBG-GFP viral vector. The hepatocytes were isolated 2 weeks post injection.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:38:29.667.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Michael Saikali
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-01 02:35:46	ID requested
1	2023-03-10 23:32:52	announced
⏵ 2	2023-11-14 08:38:30	announced	2023-11-14: Updated project metadata.

Arif W, Mathur B, Saikali MF, Chembazhi UV, Toohill K, Song YJ, Hao Q, Karimi S, Blue SM, Yee BA, Van Nostrand EL, Bangru S, Guzman G, Yeo GW, Prasanth KV, Anakk S, Cummins CL, Kalsotra A, Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death. Nat Commun, 14(1):551(2023) [pubmed]

submitter keyword: SRSF1, liver, hepatocyte, splicing

Carolyn Cummins
contact affiliation	Leslie Dan Faculty of Pharmacy, University of Toronto
contact email	Carolyn.cummins@utoronto.ca
lab head
Michael Saikali
contact affiliation	University of Toronto
contact email	michael.saikali@mail.utoronto.ca
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/2023/03/PXD027035

PRIDE project URI

• PRIDE
  1. PXD027035
     1. Label: PRIDE project
     2. Name: Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death