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J. Biol. Chem., Vol. 283, Issue 18, 12136-12145, May 2, 2008

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Bound Nucleotide Controls the Endonuclease Activity of Mismatch Repair Enzyme MutL^*

Kenji Fukui, Masami Nishida, Noriko Nakagawa, Ryoji Masui, and Seiki Kuramitsu¹

From the RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148 and the Department of Biological Sciences, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan

DNA mismatch repair corrects mismatched base pairs mainly caused by replication error. Recent studies revealed that human MutL endonuclease, hPMS2, plays an essential role in the repair. However, there has been little biochemical analysis of the MutL endonuclease. In particular, it is unknown for what the MutL utilizes ATP binding and hydrolyzing activity. Here we report the detailed functional analysis of Thermus thermophilus MutL (ttMutL). ttMutL exhibited an endonuclease activity that decreased on alteration of Asp-364 in ttMutL to Asn. The biochemical characteristics of ttMutL were significantly affected on ATP binding, which suppressed nonspecific DNA digestion and promoted the mismatch- and MutS-dependent DNA binding. The inactivation of the cysteinyl residues in the C-terminal domain resulted in the perturbation in ATP-dependent regulation of the endonuclease activity, although the ATP-binding motif is located in the N-terminal domain. Complementation experiments revealed that the endonuclease activity of ttMutL and its regulation by ATP binding are necessary for DNA repair in vivo.

Received for publication, January 7, 2008 , and in revised form, February 25, 2008.

^* This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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 Figs. 1 and 2.

¹ To whom correspondence should be addressed. Tel.: 81-791-58-2891; Fax: 81-791-58-2892; E-mail: kuramitu{at}bio.sci.osaka-u.ac.jp.

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