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J. Biol. Chem., Vol. 280, Issue 27, 25450-25460, July 8, 2005

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Analysis of the DNA Substrate Specificity of the Human BACH1 Helicase Associated with Breast Cancer^*

Rigu Gupta, Sudha Sharma, Joshua A. Sommers, Zhe Jin, Sharon B. Cantor, and Robert M. Brosh, Jr.¶

From the Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224 and the Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

We have investigated the DNA substrate specificity of BACH1 (BRCA1-associated C-terminal helicase). The importance of various DNA structural elements for efficient unwinding by purified recombinant BACH1 helicase was examined. The results indicated that BACH1 preferentially binds and unwinds a forked duplex substrate compared with a duplex flanked by only one single-stranded DNA (ssDNA) tail. In support of its DNA substrate preference, helicase sequestration studies revealed that BACH1 can be preferentially trapped by forked duplex molecules. BACH1 helicase requires a minimal 5 ' ssDNA tail of 15 nucleotides for unwinding of conventional duplex DNA substrates; however, the enzyme is able to catalytically release the third strand of the homologous recombination intermediate D-loop structure irrespective of DNA tail status. In contrast, BACH1 completely fails to unwind a synthetic Holliday junction structure. Moreover, BACH1 requires nucleic acid continuity in the 5 ' ssDNA tail of the forked duplex substrate within six nucleotides of the ssDNA-dsDNA junction to initiate efficiently DNA unwinding. These studies provide the first detailed information on the DNA substrate specificity of BACH1 helicase and provide insight to the types of DNA structures the enzyme is likely to act upon to perform its functions in DNA repair or recombination.

Received for publication, February 22, 2005 , and in revised form, May 3, 2005.

^* This work was supported in part by a Mary Kay Ash Foundation grant (to S. B. C.). 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 Figs. 1 and 2.

^¶ To whom correspondence should be addressed: Laboratory of Molecular Gerontology, NIA, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8578; Fax: 410-558-8157; E-mail: BroshR{at}grc.nia.nih.gov.

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