Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination
Summary: The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723003078 |
| _version_ | 1797860394662887424 |
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| author | Yi-Chang Wang Andrew A. Kelso Adak Karamafrooz Yi-Hsuan Chen Wei-Kai Chen Chun-Ting Cheng Yue Qi Long Gu Linda Malkas Angelo Taglialatela Hsing-Jien Kung George-Lucian Moldovan Alberto Ciccia Jeremy M. Stark David K. Ann |
| author_facet | Yi-Chang Wang Andrew A. Kelso Adak Karamafrooz Yi-Hsuan Chen Wei-Kai Chen Chun-Ting Cheng Yue Qi Long Gu Linda Malkas Angelo Taglialatela Hsing-Jien Kung George-Lucian Moldovan Alberto Ciccia Jeremy M. Stark David K. Ann |
| author_sort | Yi-Chang Wang |
| collection | DOAJ |
| description | Summary: The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments. |
| first_indexed | 2024-04-09T21:45:08Z |
| format | Article |
| id | doaj.art-02cf18b55c154e37b1ee31164012f9d4 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T21:45:08Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-02cf18b55c154e37b1ee31164012f9d42023-03-25T05:10:49ZengElsevierCell Reports2211-12472023-04-01424112296Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitinationYi-Chang Wang0Andrew A. Kelso1Adak Karamafrooz2Yi-Hsuan Chen3Wei-Kai Chen4Chun-Ting Cheng5Yue Qi6Long Gu7Linda Malkas8Angelo Taglialatela9Hsing-Jien Kung10George-Lucian Moldovan11Alberto Ciccia12Jeremy M. Stark13David K. Ann14Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USAIrell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USADepartment of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USADepartment of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USAIrell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USADepartment of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USAIrell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USADepartment of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USADepartment of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USAGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROCDepartment of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY 10032, USADepartment of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USADepartment of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA; Corresponding authorSummary: The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments.http://www.sciencedirect.com/science/article/pii/S2211124723003078CP: Molecular biology |
| spellingShingle | Yi-Chang Wang Andrew A. Kelso Adak Karamafrooz Yi-Hsuan Chen Wei-Kai Chen Chun-Ting Cheng Yue Qi Long Gu Linda Malkas Angelo Taglialatela Hsing-Jien Kung George-Lucian Moldovan Alberto Ciccia Jeremy M. Stark David K. Ann Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination Cell Reports CP: Molecular biology |
| title | Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination |
| title_full | Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination |
| title_fullStr | Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination |
| title_full_unstemmed | Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination |
| title_short | Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination |
| title_sort | arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone h4 translation and promoting pcna ubiquitination |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723003078 |
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