Publication Date
2-9-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-35932-3
PMID
36759613
PMCID
PMC9911759
PubMedCentral® Posted Date
2-9-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Animals, Mice, RNA Splicing Factors, Non-alcoholic Fatty Liver Disease, RNA, Serine-Arginine Splicing Factors, RNA, Messenger, Alternative Splicing
Abstract
Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that 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 associated with 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. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis, illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how the accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver damage.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Nephrology Commons
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