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.


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


  • Proliferating Cell Nuclear Antigen
  • Histones