The promoters for human DNA-PKcs (PRKDC) and MCM4:: Divergently transcribed genes located at chromosome 8 band q11

A 30-kb genomic segment containing the promoter and first 9 exons of PRKDC, the gene encoding the catalytic subunit (DNA-PKcs,) of the human DNA-activated protein kinase, DNA-PK, was isolated and partially sequenced. Sequence comparison with the NCBI nonredundant database revealed the locations of the first 13 exons of the upstream gene, MCM4. MCM4 is an essential component of a protein complex that prevents DNA from being replicated more than once per cell cycle. The MCM4 and DNA-PKcs, promoters are in CPG islands separated by similar to 700 bp, and transcription from each initiates at multiple, closely spaced sites. Both promoters lack TATA boxes, and the MCM4 promoter also lacks an initiator (Inr) element but has an inverted CCAAT box. The DNA-PKcs, promoter has an Inr-like sequence as well as a downstream MED-1 element. The two promoters appear to function independently, as sequences required for core promoter activity do not overlap, and sequences extending into the 5' region of each gene had little or no effect on transcription of the other gene, as shown in transient transfection assays. The arrangement of the PRKDC/MCM4 gene pair is similar to that of the ATM/ E14(NPAT) gene pair. ATM, the product of the gene mutated in ataxia telangiectasia, and DNA-PKcs, function in pathways that detect or repair DNA damage and are members of a family of large, serine/threonine kinases that are closely related to phosphatidylinositol 3 kinases. (C) 1998 Academic Press.