Identification of a novel transcriptional repressor element located in the first intron of the human BRCA1 gene.
Loss or lowered expression of BRCA1 in non-familial breast cancer has been shown in several recent studies. Understanding how BRCA1 expression is regulated should provide new insights into the role of BRCA1 in sporadic breast cancer. We have recently identified a critical 18-base pair (bp) DNA element within the minimal BRCA1 promoter whereupon the formation of a specific protein-DNA complex and transcription of BRCA1 is dependent. We now report a non tissue-specific transcriptional repressor activity, located more than 500 bp into the first intron of BRCA1. Progressive deletions from the 3'-end of intron 1 and reporter gene assays localized the repressor activity to an 83-bp region. Electrophoretic mobility shift assays with this 83 bp DNA and various sub-fragments of it showed binding of nuclear proteins to a 36 bp BstNI-BseRI fragment. Functional transcriptional repression by this 36 bp DNA could be conferred on a heterologous thymidine kinase promoter. Analysis of multiple reporter gene constructs containing the BRCA1 genomic region driving transcription in both directions suggests that the putative negative regulatory element functions to block transcription only in the BRCA1 direction, although the promoter is shared by the divergently transcribed NBR2 gene.
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Breast Cancer Prevention Program, The Toronto Hospital, Oncology Research Laboratories, Ontario M5G 2M9, Canada.
Goss
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D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1 / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014157:Transcription Factors; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C107422:NBR2 lncRNA, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors