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Division of Biology, California Institute of Technology, Pasadena, CA 91125

Address correspondence to William G. Dunphy, Division of Biology 216-76, California Institute of Technology, 1200 E. California Blvd., Pasadena, CA 91125. Tel.: (626) 395-8458. Fax: (626) 795-7563. email: dunphy{at}cco.caltech.edu

Bloom's syndrome (BS), a disorder associated with genomic instability and cancer predisposition, results from defects in the Bloom's helicase (BLM) protein. In BS cells, chromosomal abnormalities such as sister chromatid exchanges occur at highly elevated rates. Using Xenopus egg extracts, we have studied Xenopus BLM (Xblm) during both unperturbed and disrupted DNA replication cycles. Xblm binds to replicating chromatin and becomes highly phosphorylated in the presence of DNA replication blocks. This phosphorylation depends on Xenopus ATR (Xatr) and Xenopus Rad17 (Xrad17), but not Claspin. Xblm and Xenopus topoisomerase III (Xtop3) interact in a regulated manner and associate with replicating chromatin interdependently. Immunodepletion of Xblm from egg extracts results in accumulation of chromosomal DNA breaks during both normal and perturbed DNA replication cycles. Disruption of the interaction between Xblm and Xtop3 has similar effects. The occurrence of DNA damage in the absence of Xblm, even without any exogenous insult to the DNA, may help to explain the genesis of chromosomal defects in BS cells.

Key Words: RecQ helicase; ATR; Rad17; DNA replication; DNA damage

Abbreviations used in this paper: BLM, Bloom's helicase; BS, Bloom's syndrome; SCE, sister chromatid exchange; Xatr, Xenopus ATR; Xblm, Xenopus BLM; Xrad17, Xenopus Rad17; Xtop3, Xenopus topoisomerase III.

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