Structure and function of the human Werner syndrome gene promoter: evidence for transcriptional modulation.
The Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by mutations in a novel member ( WRN ) of the RecQ family of helicases. Somatic WS cells are hypermutable and have elongated S phases, suggesting possible defects in DNA replication and/or repair. As an initial approach to the investigation of how this locus might be responsive to DNA damage, we determined the structure of the human WRN promoter. The WRN promoter region has two transcription initiation sites and exhibits several features characteristic of so-called constitutive promoters, including the absence of TATA and CAAT boxes. A luciferase reporter assay revealed that the upstream promoter was used 2-10-fold less frequently than the downstream promoter, the variation being a function of cell type. The activity of the WRN promoter was dramatically reduced in cells from WS patients. The reduction of activity was not seen in three other promoters tested, including one TATA-less promoter and one TATA-containing promoter. This is consistent with the presence of a positive regulatory mechanism of WRN expression.
Department of Genetics and Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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L
Wang
K E
KE
Hunt
G M
GM
Martin
J
J
Oshima
D001483:Base Sequence; D002461:Cell Line, Transformed; D002874:Chromosome Mapping; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D014158:Transcription, Genetic; D014898:Werner Syndrome / Q000235:genetics*
D012333:RNA, Messenger