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J. Biol. Chem., Vol. 283, Issue 1, 145-154, January 4, 2008

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hMSH4-hMSH5 Adenosine Nucleotide Processing and Interactions with Homologous Recombination Machinery^*

Timothy Snowden, Kang-Sup Shim, Christoph Schmutte, Samir Acharya, and Richard Fishel¹

From the Genetics and Molecular Biology Program, Kimmel Cancer Center, Philadelphia, Pennsylvania 19107 and the Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics, The Ohio State University School of Medicine and Public Health, Columbus, Ohio 43210

We have previously demonstrated that the human heterodimeric meiosis-specific MutS homologs, hMSH4-hMSH5, bind uniquely to a Holliday Junction and its developmental progenitor (Snowden, T., Acharya, S., Butz, C., Berardini, M., and Fishel, R. (2004) Mol. Cell 15, 437–451). ATP binding by hMSH4-hMSH5 resulted in the formation of a sliding clamp that dissociated from the Holliday Junction crossover region embracing two duplex DNA arms. The loading of multiple hMSH4-hMSH5 sliding clamps was anticipated to stabilize the interaction between parental chromosomes during meiosis double-stranded break repair. Here we have identified the interaction region between the individual subunits of hMSH4-hMSH5 that are likely involved in clamp formation and show that each subunit of the heterodimer binds ATP. We have determined that ADPATP exchange is uniquely provoked by Holliday Junction recognition. Moreover, the hydrolysis of ATP by hMSH4-hMSH5 appears to occur after the complex transits the open ends of model Holliday Junction oligonucleotides. Finally, we have identified several components of the double-stranded break repair machinery that strongly interact with hMSH4-hMSH5. These results further underline the function(s) and interactors of hMSH4-hMSH5 that ensure accurate chromosomal repair and segregation during meiosis.

Received for publication, May 16, 2007 , and in revised form, October 18, 2007.

^* This work was supported by National Research Service Award T32-CA09662 and National Institutes of Health Grants CA67007 and GM62556. 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.

¹ To whom correspondence should be addressed: Wiseman 485N, 400 W. 12th Ave., Columbus, OH 43210. Tel.: 614-292-2484; E-mail: rfishel{at}osu.edu.

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