Gene replacement with the human BRCA1 locus: Tissue specific expression and rescue of embryonic lethality in mice

Timothy F Lane*, Chenwei Lin, Melissa A. Brown, Ellen Solomon, Philip Leder

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

We have generated transgenic mice that harbor a 140 kb genomic fragment of the human BRCA1 locus (TgN·BRCA1(GEN)). We find that the transgene directs appropriate expression of human BRCA1 transcripts in multiple mouse tissues, and that human BRCA1 protein is expressed and stabilized following exposure to DNA damage. Such mice are completely normal, with no overt signs of BRCA1 toxicity commonly observed when BRCA1 is expressed from heterologous promoters. Most importantly, however, the transgene rescues the otherwise lethal phenotype associated with the targeted hypomorphic allele (Brca1(ΔexIISA)). Brca1(-/-); TgN·BRCA1(GEN) bigenic animals develop normally and can be maintained as a distinct line. These results show that a 140 kb fragment of chromosome 17 contains all elements necessary for the correct expression, localization, and function of the BRCA1 protein. Further, the model provides evidence that function and regulation of the human BRCA1 gene can be studied and manipulated in a genetically tractable mammalian system.

Original languageEnglish (US)
Pages (from-to)4085-4090
Number of pages6
JournalOncogene
Volume19
Issue number36
DOIs
StatePublished - Aug 24 2000

Keywords

  • BRCA1
  • Gene transfer
  • Transgenic
  • Tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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