Recent studies have identified upregulation of the dyskeratosis congenita 1 (DKC1) gene in association with various sporadic cancers. Whole genome analyses have suggested that DKC1 may be regulated by the c-MYC oncoprotein. c-MYC is among the most commonly deregulated proteins in human cancer. However, controversy remains as to whether DKC1 is a direct or indirect target of c-MYC. Using human and rodent cell lines expressing conditionally active c-MYC transgenes, we show that c-MYC activation is associated with relatively acute induction of DKC1 expression. Chromatin immunoprecipitation assays reveal c-MYC binding to two distinct, phylogenetically conserved regions within the DKC1 promoter and intron one. We further demonstrate that c-MYC-mediated DkcI transcription can occur in the absence of de nouo protein synthesis. These data indicate that DKC1 is a direct and conserved transcriptional target of c-MYC, and suggest a biologic basis for DKC1 overexpression in neoplasia. (c) 2007 Elsevier Inc. All rights reserved.