We have isolated a new human RING-finger gene (RNF4) that encodes a 190-amino-acid protein. RNF4, in addition to the carboxyl-terminally located RING-finger motif, contains two putative nuclear localization signals and stretches of acidic amino acids that are similar to the activation domains of some transcription factors. RNF4 was expressed at low levels in all human tissues examined, with the notable exception of very high expression in the testis. The mouse homolog of RNF4 was abundantly expressed in embryonic tissues from the earliest days postgestation and exhibited a ubiquitous pattern of expression as assessed by in situ hybridization. We have mapped RNF4 to 4p16.3, a chromosome region associated with several genetic and neoplastic diseases. RNF4 spans 47 kb, is composed of eight exons, and maps immediately proximal to the anonymous locus D4S183, between the huntingtin (HD) and the fibroblast growth factor receptor 3 (FGFR3) genes.