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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number112296
JournalCell Reports
Issue number4
StatePublished - Apr 25 2023

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

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