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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 led to a G1/S cell cycle arrest, and reduced cell viability. REXO4 associated with ribosome components and other proteins involved in rRNA metabolism. We propose a model where REXO4 is important for proper rRNA processing, which is required for ribosome biogenesis, cell cycle progression, and proliferation. REXO4 is a putative RNA exonuclease with limited characterization. The authors used in silico, cell, and molecular biology approaches to characterize its localization, associations, regulation, and function. They found that during interphase, REXO4 localizes to the nucleolus through an N-terminal nucleolar localization sequence. Whereas during mitosis, REXO4 localized to the perichromosomal layer in a Ki67-dependent manner. REXO4 was required for proper cell cycle progression, and viability. These results indicated that REXO4 is important for regulating cell proliferation.