Intranuclear trafficking

Nucleic acids and regulatory proteins involved in gene expression and DNA replication are localized in specialized subnuclear domains that can be visualized by microscopy. However, the rules that govern the compartmentalization of the nucleus into these discrete domains have been elusive. From an historical perspective, the concept of nuclear subdivisions as functional compartments initially focused on the nucleolus as the site of ribosomal gene expression and nuclear pores as gates for bidirectional exchange of RNAs and proteins between the nucleus and cytoplasm. We now recognize that specific mechanisms might coordinate the spatial organization of genes, transcripts and regulatory proteins within the nucleus. The sorting and integration of regulatory signals as well as the assembly and function of intranuclear sites are components of the mechanisms that mediate physiological control of gene expression. Examples of specialized subnuclear domains in which the machineries for gene expression and DNA replication reside include, but are not confined to, sites that support transcription, processing of gene transcripts and DNA synthesis (reviewed by Cook, 1999; Kimura et al., 1999; Lamond and Earnshaw, 1998; Leonhardt et al., 1998; Ma et al., 1998; Misteli and Spector, 1999; Misteli, 2000; Smith et al., 1999; Verschure et al., 1999; Wei et al., 1998; Zeng et al., 1998). The intranuclear organization of nucleic acids and cognate factors provides a potential mechanism to achieve the threshold concentrations for formation and sustained activity of transcription and replication complexes. Here, we present an overview of emerging evidence for mechanisms that mediate the intranuclear targeting of regulatory proteins to nuclear sites at which gene expression occurs. We also discuss findings that implicate perturbations in the intranuclear trafficking of regulatory factors in the loss of fidelity of gene expression that occurs in tumor cells.