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J. Biol. Chem., Vol. 282, Issue 43, 31484-31492, October 26, 2007

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Holliday Junction Processing Activity of the BLM-Topo III-BLAP75 Complex^*

From the Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520

BLM, the protein mutated in Bloom's syndrome, possesses a helicase activity that can dissociate DNA structures, including the Holliday junction, expected to arise during homologous recombination. BLM is stably associated with topoisomerase III (Topo III) and the BLAP75 protein. The BLM-Topo III-BLAP75 (BTB) complex can efficiently resolve a DNA substrate that harbors two Holliday junctions (the double Holliday junction) in a non-crossover manner. Here we show that the Holliday junction unwinding activity of BLM is greatly enhanced as a result of its association with Topo III and BLAP75. Enhancement of this BLM activity requires both Topo III and BLAP75. Importantly, Topo III cannot be substituted by Escherichia coli Top3, and the Holliday junction unwinding activity of BLM-related helicases WRN and RecQ is likewise impervious to Topo III and BLAP75. However, the topoisomerase activity of Topo III is dispensable for the enhancement of the DNA unwinding reaction. We have also ascertained the requirement for the BLM ATPase activity in double Holliday junction dissolution and DNA unwinding by constructing, purifying, and characterizing specific mutant variants that lack this activity. These results provide valuable information concerning how the functional integrity of the BTB complex is governed by specific protein-protein interactions among the components of this complex and the enzymatic activities of BLM and Topo III.

Received for publication, July 25, 2007 , and in revised form, August 27, 2007.

^* This work was supported by National Institutes of Health Grants CA110415, ES015252, and ES015632, training Grant T32 GM08735, and United States Department of Defense Predoctoral Fellowship W81XWH-04-1-0410. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ Present address: Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108.

² To whom correspondence should be addressed: Dept. of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar St., C130 Sterling Hall of Medicine, New Haven, CT 06520-8024. Tel.: 203-785-4553; Fax: 203-785-6404; E-mail: Patrick.Sung{at}yale.edu.

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