Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death

Waqar Arif, Bhoomika Mathur, Michael F. Saikali, Ullas V. Chembazhi, Katelyn Toohill, You Jin Song, Qinyu Hao, Saman Karimi, Steven M. Blue, Brian A. Yee, Eric L. Nostrand, Sushant Bangru, Grace Guzman, Gene W. Yeo, Kannanganattu V. Prasanth, Sayeepriyadarshini Anakk, Carolyn L. Cummins and Auinash Kalsotra ()
Additional contact information
Waqar Arif: University of Illinois Urbana-Champaign
Bhoomika Mathur: University of Illinois Urbana-Champaign
Michael F. Saikali: University of Toronto
Ullas V. Chembazhi: University of Illinois Urbana-Champaign
Katelyn Toohill: University of Illinois Urbana-Champaign
You Jin Song: University of Illinois Urbana-Champaign
Qinyu Hao: University of Illinois Urbana-Champaign
Saman Karimi: University of Illinois Hospital and Health Science Chicago
Steven M. Blue: University of California at San Diego
Brian A. Yee: University of California at San Diego
Eric L. Nostrand: University of California at San Diego
Sushant Bangru: University of Illinois Urbana-Champaign
Grace Guzman: University of Illinois Hospital and Health Science Chicago
Gene W. Yeo: University of California at San Diego
Kannanganattu V. Prasanth: University of Illinois Urbana-Champaign
Sayeepriyadarshini Anakk: University of Illinois Urbana-Champaign
Carolyn L. Cummins: University of Toronto
Auinash Kalsotra: University of Illinois Urbana-Champaign

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35932-3

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