DNA-PK is a moderately abundant serine/threonine protein kinase found in the nucleus of a wide range of eukaryotic cells. It is one of the few known cellular enzymes whose activity is regulated directly by DNA. Many DNA binding proteins, including a number of transcription factors, are substrates for DNA-PK in vitro. We suggest that this kinase may coordinate signal transduction pathways and nuclear events, including transcription, in response to changes in DNA or chromatin state.