title: Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.
abstract: The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.
authors.affiliation: Department of Human Genetics, University of Wurzburg, Wurzburg, Germany. daniel.meier@biozentrum.uni-wuerzburg.de
authors.forename: Daniel
authors.initials: D
authors.lastname: Meier
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
mesh_terms: D001665:Binding Sites; D004265:DNA Helicases / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005199:Fanconi Anemia / Q000235:genetics; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics; D052239:Fanconi Anemia Complementation Group E Protein / Q000235:genetics; D052219:Fanconi Anemia Complementation Group F Protein / Q000235:genetics; D052241:Fanconi Anemia Complementation Group G Protein / Q000235:genetics; D052240:Fanconi Anemia Complementation Group L Protein / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta
chemical_list: C498471:FANCA protein, human; C515775:FANCB protein, human; C497651:FANCC protein, human; C499907:FANCE protein, human; C499901:FANCF protein, human; C499909:FANCG protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D052239:Fanconi Anemia Complementation Group E Protein; D052219:Fanconi Anemia Complementation Group F Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein; C518295:FANCM protein, human; D004265:DNA Helicases