Human REXO4 is Required for Cell Cycle Progression

Human REXO4 is a poorly characterized exonuclease that is overexpressed in human cancers. To better understand the function of REXO4 and its relationship to cellular proliferation, we have undertaken multidisciplinary approaches to characterize its cell cycle phase-dependent subcellular localization and the cis determinants required for this localization, its importance to cell cycle progression and cell viability, its protein-protein association network, and its activity. We show that the localization of REXO4 to the nucleolus in interphase depends on an N-terminal nucleolar localization sequence and that its localization to the perichromosomal layer of mitotic chromosomes is dependent on Ki67. Depletion of REXO4 leads to a G1/S cell cycle arrest, and reduced cell viability. REXO4 associates with ribosome components and other proteins involved in RNA metabolism. Overall, our results show that REXO4 is dynamically localized to distinct RNA-containing structures throughout the cell cycle, associates with RNA metabolism proteins, and is required for proper cell cycle progression and cell viability.