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

doi:10.1016/j.celrep.2023.112296

Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination

Cell Rep. 2023 Apr 25;42(4):112296. doi: 10.1016/j.celrep.2023.112296. Epub 2023 Mar 23.

Authors

Affiliations

¹ Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
² Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.
³ 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.
⁴ Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁵ 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.
⁶ Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁷ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC.
⁸ Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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. Electronic address: dann@coh.org.

Abstract

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.

Keywords: CP: Molecular biology; HLTF; K63-linked polyubiquitination; PCNA; S phase; arginine; genotoxin resistance; histone H4; replication stress; translation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

DNA Damage*
DNA Replication
Histones* / metabolism
Proliferating Cell Nuclear Antigen / metabolism
Ubiquitination

Substances

Proliferating Cell Nuclear Antigen
Histones

Abstract

Publication types

MeSH terms

Substances

Grants and funding