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

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 fo...

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Autores principales: Arif, Waqar, Mathur, Bhoomika, Saikali, Michael F., Chembazhi, Ullas V., Toohill, Katelyn, Song, You Jin, Hao, Qinyu, Karimi, Saman, Blue, Steven M., Yee, Brian A., Van Nostrand, Eric L., Bangru, Sushant, Guzman, Grace, Yeo, Gene W., Prasanth, Kannanganattu V., Anakk, Sayeepriyadarshini, Cummins, Carolyn L., Kalsotra, Auinash
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911759/
https://www.ncbi.nlm.nih.gov/pubmed/36759613
http://dx.doi.org/10.1038/s41467-023-35932-3
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author Arif, Waqar
Mathur, Bhoomika
Saikali, Michael F.
Chembazhi, Ullas V.
Toohill, Katelyn
Song, You Jin
Hao, Qinyu
Karimi, Saman
Blue, Steven M.
Yee, Brian A.
Van Nostrand, Eric L.
Bangru, Sushant
Guzman, Grace
Yeo, Gene W.
Prasanth, Kannanganattu V.
Anakk, Sayeepriyadarshini
Cummins, Carolyn L.
Kalsotra, Auinash
author_facet Arif, Waqar
Mathur, Bhoomika
Saikali, Michael F.
Chembazhi, Ullas V.
Toohill, Katelyn
Song, You Jin
Hao, Qinyu
Karimi, Saman
Blue, Steven M.
Yee, Brian A.
Van Nostrand, Eric L.
Bangru, Sushant
Guzman, Grace
Yeo, Gene W.
Prasanth, Kannanganattu V.
Anakk, Sayeepriyadarshini
Cummins, Carolyn L.
Kalsotra, Auinash
author_sort Arif, Waqar
collection PubMed
description 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.
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spelling pubmed-99117592023-02-11 Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death Arif, Waqar Mathur, Bhoomika Saikali, Michael F. Chembazhi, Ullas V. Toohill, Katelyn Song, You Jin Hao, Qinyu Karimi, Saman Blue, Steven M. Yee, Brian A. Van Nostrand, Eric L. Bangru, Sushant Guzman, Grace Yeo, Gene W. Prasanth, Kannanganattu V. Anakk, Sayeepriyadarshini Cummins, Carolyn L. Kalsotra, Auinash Nat Commun Article 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. Nature Publishing Group UK 2023-02-09 /pmc/articles/PMC9911759/ /pubmed/36759613 http://dx.doi.org/10.1038/s41467-023-35932-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Arif, Waqar
Mathur, Bhoomika
Saikali, Michael F.
Chembazhi, Ullas V.
Toohill, Katelyn
Song, You Jin
Hao, Qinyu
Karimi, Saman
Blue, Steven M.
Yee, Brian A.
Van Nostrand, Eric L.
Bangru, Sushant
Guzman, Grace
Yeo, Gene W.
Prasanth, Kannanganattu V.
Anakk, Sayeepriyadarshini
Cummins, Carolyn L.
Kalsotra, Auinash
Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
title Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
title_full Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
title_fullStr Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
title_full_unstemmed Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
title_short Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
title_sort splicing factor srsf1 deficiency in the liver triggers nash-like pathology and cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911759/
https://www.ncbi.nlm.nih.gov/pubmed/36759613
http://dx.doi.org/10.1038/s41467-023-35932-3
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