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Snail/Slug family proteins have been identified in diverse species of both vertebrates and invertebrates. The proteins contain four to six zinc fingers and function as DNA-binding transcriptional regulators. Various members of the family have been demonstrated to regulate cell movement, neural cell fate, left-right asymmetry, cell cycle, and apoptosis. However, the molecular mechanisms of how these regulators function and the target genes involved are largely unknown. In this report, we demonstrate that human Slug (hSlug) is a repressor and modulates both activator-dependent and basal transcription. The repression depends on the C-terminal DNA-binding zinc fingers and on a separable repression domain located in the N terminus. This domain may recruit histone deacetylases to modify the chromatin and effect repression. Protein localization study demonstrates that hSlug is present in discrete foci in the nucleus. This subnuclear pattern does not colocalize with the PML foci or the coiled bodies. Instead, the hSlug foci overlap extensively with areas of the SC-35 staining, some of which have been suggested to be sites of active splicing or transcription. These results lead us to postulate that hSlug localizes to target promoters, where activation occurs, to repress basal and activator-mediated transcription.