ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response.

Autor: Lim LQJ; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Adler L; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Hajaj E; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.; Department of Medicine D, Beilinson Hospital, Petah Tikva, Israel., Soria LR; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Perry RB; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel., Darzi N; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Brody R; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Furth N; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Lichtenstein M; Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel., Bab-Dinitz E; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Porat Z; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Melman T; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Brandis A; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Malitsky S; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Itkin M; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Aylon Y; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Ben-Dor S; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Orr I; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Pri-Or A; The De Botton Protein Profiling Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel., Seger R; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Shaul Y; Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel., Ruppin E; Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA., Oren M; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Perez M; Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA., Meier J; Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA., Brunetti-Pierri N; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.; Department of Translational Medicine, Medical Genetics, University of Naples Federico II, Naples, Italy.; Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy., Shema E; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel., Ulitsky I; Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel., Erez A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. ayelet.erez@weizmann.ac.il.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Jul; Vol. 6 (7), pp. 1294-1309. Date of Electronic Publication: 2024 Jun 10.
DOI: 10.1038/s42255-024-01060-5
Abstrakt: Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) in multiple tumors is associated with a poor prognosis partly because of the metabolic diversion of cytosolic aspartate for pyrimidine synthesis, supporting proliferation and mutagenesis owing to nucleotide imbalance. Here, we find that prolonged loss of ASS1 promotes DNA damage in colon cancer cells and fibroblasts from subjects with citrullinemia type I. Following acute induction of DNA damage with doxorubicin, ASS1 expression is elevated in the cytosol and the nucleus with at least a partial dependency on p53; ASS1 metabolically restrains cell cycle progression in the cytosol by restricting nucleotide synthesis. In the nucleus, ASS1 and ASL generate fumarate for the succination of SMARCC1, destabilizing the chromatin-remodeling complex SMARCC1-SNF5 to decrease gene transcription, specifically in a subset of the p53-regulated cell cycle genes. Thus, following DNA damage, ASS1 is part of the p53 network that pauses cell cycle progression, enabling genome maintenance and survival. Loss of ASS1 contributes to DNA damage and promotes cell cycle progression, likely contributing to cancer mutagenesis and, hence, adaptability potential.
(© 2024. The Author(s).)
Databáze: MEDLINE
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