Modulation of Werner syndrome protein function by a single mutation in the conserved  RQC domain

doi:10.1074/jbc.M506112200

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Papers In Press, published online ahead of print September 7, 2005
J. Biol. Chem, 10.1074/jbc.M506112200
Submitted on June 3, 2005
Revised on August 22, 2005
Accepted on September 7, 2005

Modulation of Werner syndrome protein function by a single mutation in the conserved RQC domain

Jae Wan Lee, Rika Kusumoto, Kevin M. Doherty, Guang-Xin Lin, Wangyong Zeng, Wen-Hsing Cheng, Cayetano von Kobbe, Robert M. Brosh . Jr, Jin-Shan Hu, and Vilhelm A. Bohr

Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224

Corresponding Author: vbohr{at}nih.gov

Naturally occurring mutations in the human RecQ3 gene result in truncated Werner protein (WRN) and manifest as a rare premature aging disorder, Werner syndrome. Cellular and biochemical studies suggest a multifaceted role of WRN in DNA replication, DNA repair, recombination, and telomere maintenance. The RecQ C-terminal (RQC) domain of WRN was previously determined to be the major site of interaction for DNA and proteins. Using site-directed mutagenesis in the WRN RQC domain, we determined which amino acids might be playing a critical role in WRN function. A site-directed mutation at residue K1016 significantly decreased WRN binding to fork or bubble DNA substrates. Moreover, the K1016 mutation markedly reduced WRN helicase activity on fork, D-loop, and Holliday junction substrates in addition to significantly reducing the ability of WRN to stimulate FEN-1 incision activities. Our nuclear magnetic resonance data on the three dimensional structure of the wild-type RQC and K1016 mutant proteins display a remarkable similarity in their structures. Thus, DNA binding mediated by the RQC domain is crucial for WRN helicase and its coordinated functions.

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