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J. Biol. Chem., Vol. 277, Issue 32, 28641-28647, August 9, 2002

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BRCA1 Facilitates Microhomology-mediated End Joining of DNA Double Strand Breaks^*

Qing Zhong, Chi-Fen Chen, Phang-Lang Chen, and Wen-Hwa Lee^§

From the Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245

BRCA1 is critical for the maintenance of genomic stability, in part through its interaction with the Rad50·Mre11·Nbs1 complex, which occupies a central role in DNA double strand break repair mediated by nonhomologous end joining (NHEJ) and homologous recombination. BRCA1 has been shown to be required for homology-directed recombination repair. However, the role of BRCA1 in NHEJ, a critical pathway for the repair of double strand breaks and genome stability in mammalian cells, remains elusive. Here, we established a pair of mouse embryonic fibroblasts (MEFs) derived from 9.5-day-old embryos with genotypes Brca1^+/+:p53^/ or Brca1^/:p53^/. The Brca1^/:p53^/ MEFs appear to be extremely sensitive to ionizing radiation. The contribution of BRCA1 in NHEJ was evaluated in these cells using three different assay systems. First, transfection of a linearized plasmid in which expression of the reporter gene required precise end joining indicated that Brca1^/ MEFs display a moderate deficiency when compared with Brca1^+/+ cells. Second, using a retrovirus infection assay dependent on NHEJ, a 5-10-fold reduction in retroviral integration efficiency was observed in Brca1^/ MEFs when compared with the Brca1^+/+ MEFs. Third, Brca1^/ MEFs exhibited a 50-100-fold deficiency in microhomology-mediated end-joining activity of a defined chromosomal DNA double strand break introduced by a rare cutting endonuclease I-SceI. These results provide evidence that Brca1 has an essential role in microhomology-mediated end joining and suggest a novel molecular basis for its caretaker role in the maintenance of genome integrity.

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