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Published online 26 March 2004

Nucleic Acids Research, 2004, Vol. 32, No. 6 1886-1893
© 2004 Oxford University Press

Structural and functional analysis of Mre11-3

L. Matthew Arthur, Karin Gustausson1, Karl-Peter Hopfner2, Christian T. Carson3, Travis H. Stracker3, Annette Karcher2, Diana Felton4, Matthew D. Weitzman3, John Tainer1,4 and James P. Carney*

Radiation Oncology Research Laboratory, Department of Radiation Oncology, Molecular and Cell Biology Graduate Program and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA, 1 Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute and 3 Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA, 2 Gene Center and Institute of Biochemistry, University of Munich, Munich, Germany and 4 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

*To whom correspondence should be addressed. Tel: +1 410 706 4276; Fax: +1 410 706 6138; Email: jcarney{at}som.umaryland.edu
Present address:
Travis H. Stracker, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

Received December 23, 2003; Revised and Accepted February 27, 2004

The Mre11, Rad50 and Nbs1 proteins make up the conserved multi-functional Mre11 (MRN) complex involved in multiple, critical DNA metabolic processes including double-strand break repair and telomere maintenance. The Mre11 protein is a nuclease with broad substrate recognition, but MRN-dependent processes requiring the nuclease activity are not clearly defined. Here, we report the functional and structural characterization of a nuclease-deficient Mre11 protein termed mre11-3. Importantly, the hmre11-3 protein has wild-type ability to bind DNA, Rad50 and Nbs1; however, nuclease activity was completely abrogated. When expressed in cell lines from patients with ataxia telangiectasia-like disorder (ATLD), hmre11-3 restored the formation of ionizing radiation-induced foci. Consistent with the biochemical results, the 2.3 Å crystal structure of mre11-3 from Pyrococcus furiosus revealed an active site structure with a wild-type-like metal-binding environment. The structural analysis of the H85L mutation provides a detailed molecular basis for the ability of mre11-3 to bind but not hydrolyze DNA. Together, these results establish that the mre11-3 protein provides an excellent system for dissecting nuclease-dependent and independent functions of the Mre11 complex.


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