BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair

Derek W. Abbott, Marilyn E. Thompson, Cheryl Robinson-Benion, Gail Tomlinson, Roy A. Jensen, Jeffrey T. Holt

Research output: Contribution to journalArticle

198 Scopus citations

Abstract

The breast cancer predisposition genes, BRCA1 and BRCA2, are responsible for the vast majority of hereditary breast cancer. Although BRCA2 functions to help the cell repair double-stranded DNA breaks, the function of BRCA1 remains enigmatic. Here, we develop a human genetic system to study the role of BRCA1 in oxidative DNA damage. We show that human cancer cells containing mutated BRCA1 are hypersensitive to ionizing radiation. This hypersensitivity can be reversed by the expression of forms of BRCA1 that are not growth suppressing. Reversal of hypersensitivity requires the ring finger of BRCA1, its transactivation domain, and its BRCT domain. Lastly, we show that unlike BRCA2, BRCA1 does not function in the repair of double-stranded DNA breaks. Instead, it functions in transcription-coupled DNA repair (TCR). TCR ability correlated with radioresistance as cells containing BRCA1 showed both increased TCR and radioresistance, whereas cells without BRCA1 showed decreased TCR and radiosensitivity. These findings give physiologic significance to the interaction of BRCA1 with the basal transcription machinery.

Original languageEnglish (US)
Pages (from-to)18808-18812
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number26
DOIs
StatePublished - Jun 25 1999

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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