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MBC in Press, published online ahead of print February 6, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0975

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Submitted on September 28, 2007
Revised on January 16, 2008
Accepted on January 29, 2008

A Mutant Allele of MRE11 Found in Mismatch Repair Deficient Tumor Cells Suppresses the Cellular Response to DNA Replication Fork Stress in a Dominant Negative Manner

Qin Wen,* Jennifer Scorah,*{dagger} Geraldine Phear, Gary Rodgers, Sheila Rodgers, and Mark Meuth

Institute for Cancer Studies, University of Sheffield, School of Medicine and Biomedical Sciences, Sheffield S10 2RX, United Kingdom

Monitoring Editor: Orna Cohen-Fix

The interaction of Ataxia-Telangiectasia Mutated (ATM) and the Mre11/Nbs1/Rad50 (MRN) complex is critical for the response of cells to DNA double strand breaks (DSBs), however relatively little is known of the role of these proteins in response to DNA replication stress. Here we report a mutant allele of MRE11 found in a colon cancer cell line that sensitizes cells to agents causing replication fork stress. The mutant Mre11 weakly interacts with Rad50 relative to wild type and shows little affinity for Nbs1. The mutant protein lacks 3'-5' exonuclease activity as a result of loss of part of the conserved nuclease domain, however it retains binding affinity for single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) with a 3' single-strand overhang, and fork-like structures containing ssDNA regions. In cells the mutant protein shows a time- and dose-dependent accumulation in chromatin following thymidine treatment that corresponds with increased recruitment and hyperphosphorylation of RPA. ATM autophosphorylation, Mre11 foci, and thymidine-induced homologous recombination (HR) are suppressed in cells expressing the mutant allele. Taken together, our results suggest that the mutant Mre11 suppresses the cellular response to replication stress by binding to ssDNA regions at disrupted forks and impeding replication restart in a dominant negative manner.

*These authors contributed equally to this work.

{dagger}Present address: Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.

Address correspondence to: Mark Meuth (m.meuth{at}sheffield.ac.uk)




This article has been cited by other articles:


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R. Rodriguez, L. T. Hansen, G. Phear, J. Scorah, M. Spang-Thomsen, A. Cox, T. Helleday, and M. Meuth
Thymidine Selectively Enhances Growth Suppressive Effects of Camptothecin/Irinotecan in MSI+ Cells and Tumors Containing a Mutation of MRE11
Clin. Cancer Res., September 1, 2008; 14(17): 5476 - 5483.
[Abstract] [Full Text] [PDF]


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