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[Cancer Research 63, 3049-3053, June 15, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Both DNA Topoisomerase II-binding Protein 1 and BRCA1 Regulate the G2-M Cell Cycle Checkpoint1

Kazuhiko Yamane, Junjie Chen and Timothy J. Kinsella2

Department of Radiation Oncology, Case Western Reserve University [K. Y., T. J. K.], and Ireland Comprehensive Cancer Center, University Hospitals of Cleveland [T. J. K.], Cleveland, Ohio 44106-4942, and Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. C.]

Cell cycle checkpoints play a central role in genomic stability. The human DNA topoisomerase II-binding protein 1 (TopBP1) protein contains eight BRCA1 COOH terminus motifs and shares similarities with Cut5, a yeast checkpoint Rad protein. TopBP1 also shares many features with BRCA1. We report that, when expression of TopBP1 protein is inhibited in BRCA1 mutant cells, mimicking a TopBP1, BRCA1 double-negative condition, the G2-M checkpoint is strongly abrogated and apoptosis is increased after ionizing radiation. However, a BRCA1-negative or a TopBP1-negative background resulted in only partial abrogation of the G2-M checkpoint. The BRCA1 mutant and TopBP1-reduced condition specifically destroys regulation of the Chk1 kinase but not the Chk2 kinase, suggesting involvement in the ataxia telangiectasia-related pathway. These results indicate that both TopBP1 and BRCA1 specifically regulate the G2-M checkpoint, partially compensating each function.




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