Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination
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
Affiliations
Yi-Chang Wang
Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Andrew A. Kelso
Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
Adak Karamafrooz
Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Yi-Hsuan Chen
Department 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
Wei-Kai Chen
Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
Chun-Ting Cheng
Department 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
Yue Qi
Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA
Long Gu
Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
Linda Malkas
Department 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, USA
Angelo Taglialatela
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Hsing-Jien Kung
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC
George-Lucian Moldovan
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Alberto Ciccia
Department 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, USA
Jeremy M. Stark
Department 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, USA
David K. Ann
Department 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 author
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.
