Nucleic Acids Research, 2002, Vol. 30, No. 8 1713-1724
© 2002 Oxford University Press
Ku86 autoantigen related protein-1 transcription initiates from a CpG island and is induced by p53 through a nearby p53 response element
Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, RI 02912, USA and 1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, 2-197 Moos Tower, 515 Delaware Street, Minneapolis, MN 55455, USA
The human Ku86 gene and an isoform, KARP-1 (Ku86 autoantigen related protein-1), encode overlapping, but differentially regulated, transcripts. Ku86 is constitutively transcribed at high levels and, although it plays a seminal role in DNA double-strand break repair, its expression is not induced by DNA damage. KARP-1, in contrast, is expressed constitutively only at low levels and its expression is induced by DNA damage in a p53-dependent fashion. The regulatory elements promoting KARP-1 gene expression and p53 responsiveness, however, were unknown. Here, we report that a strong DNase I hypersensitive site (DHS) resides 
25 kb upstream from the Ku86 promoter. This DHS is encompassed by a hypomethylated CpG island. Reporter assays demonstrated that this region corresponded to a promoter(s), which promoted transcription of peroxisomal trans-2-enoyl CoA reductase in the centromeric direction and KARP-1 in the telomeric direction. KARP-1 primer extension products were mapped to this CpG island in the correct transcriptional orientation confirming that KARP-1 transcription initiates from this site. Moreover, a p53 response element within the first intron of the KARP-1 transcriptional unit was identified using chromatin immunoprecipitation and antibodies specific to activated forms of p53. These data expand our understanding of this important DNA repair locus.
* To whom correspondence should be addressed. Tel: +1 612 624 5988; Fax: +1 612 625 5476; Email: hendr064{at}tc.umn.edu
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