ZCCHC4 promotes replication-dependent histone mRNA translation through interaction with the eIF3 complex

Abstract

Abstract Histone synthesis is tightly coupled with DNA replication to ensure proper chromatin assembly and genome stability. To meet the sharply elevated demand for histones during S phase, eukaryotic cells employ specialized mechanisms to translate replication-dependent (RD) histone mRNAs. These mRNAs possess distinctive features, such as specific UTR structures and the absence of poly(A) tails. Nevertheless, the molecular mechanisms controlling the translation of RD-histone mRNAs remain incompletely understood. In the current study, we report that ZCCHC4, which has been identified as the m 6 A RNA methyltransferase for 28S rRNA, is a novel regulator essential for RD-histone mRNA translation. ZCCHC4 exhibits unexpected subcellular localization of cytoplasm besides nucleus, and the cytoplasmic ZCCHC4 directly interacts with components of the translation initiation machinery. Depletion of ZCCHC4 reduces global protein translation, particularly the translation of RD histones. This translational impairment leads to insufficient histone supply, chromatin relaxation, and prolongs the S phase of the cell cycle. Moreover, ZCCHC4 knockout markedly inhibits cell proliferation, colony-forming ability, and the growth of xenograft tumors. Collectively, this study establishes a previously unrecognized role for ZCCHC4 in histone synthesis, at least in part through its interaction with eIF3, thereby sustaining histone supply during S phase in tumor cells. Our findings not only provide novel insights into histone mRNA translation control but also point to a potential role for ZCCHC4 in tumorigenesis.