Coupling arginine with DNA replication and chemoresistance

Abstract

How cells adapt DNA replication to meet amino acid demands is an active area of interest across biology. Among a broad range of functions, the extracellular arginine is needed for the availability of newly synthesized histones to promote DNA replication fork progression. We show herein that transient deprivation of extracellular arginine, but not glutamine or leucine, causes a reversible S‐phase arrest. This unexpected dynamic S‐phase arrest feature is independent of mTORC1 signaling inhibition, insufficient metabolites, endogenous de novo arginine biosynthesis, and general amino acid control pathway. Moreover, knockdown of arginyl‐tRNA‐transferase recapitulated the loss of histone H4 lysine 5 and 12 acetylation marks and the reduction of replication fork speed without inhibition of origin firing. Importantly, single round of arginine depletion and addition did not induce ATR/Chk1 activation and DNA double‐stand breaks associated γH2AX. The halt of arginine‐dependent histone H4 synthesis is therefore emerging as a “brake” for DNA replication bypassing checkpoint control. However, repeated arginine fluctuation promote the emergence of nuclear p53‐binding protein 1 bodies in the subsequent G1‐phase, creating vulnerabilities of DNA replications and can be exploited by cancer cells that promote DNA repair and resistance to genotoxic agents. Thus, intratumoral variation in the arginine microenvironment synchronizes DNA replication with therapeutic responses.