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Molecular and Cellular Biology, August 2001, p. 5142-5155, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5142-5155.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

exo1-Dependent Mutator Mutations: Model System for Studying Functional Interactions in Mismatch Repair

Neelam S. Amin,1 My-Nga Nguyen,1 Scott Oh,1 and Richard D. Kolodner1,2,3,*

Ludwig Institute for Cancer Research,1 Department of Medicine,2 and Cancer Center,3 University of California, San Diego School of Medicine, La Jolla, California 92093-0660

Received 7 February 2001/Returned for modification 11 March 2001/Accepted 20 April 2001

EXO1 interacts with MSH2 and MLH1 and has been proposed to be a redundant exonuclease that functions in mismatch repair (MMR). To better understand the role of EXO1 in mismatch repair, a genetic screen was performed to identify mutations that increase the mutation rates caused by weak mutator mutations such as exo1Delta and pms1-A130V mutations. In a screen starting with an exo1 mutation, exo1-dependent mutator mutations were obtained in MLH1, PMS1, MSH2, MSH3, POL30 (PCNA), POL32, and RNR1, whereas starting with the weak pms1 allele pms1-A130V, pms1-dependent mutator mutations were identified in MLH1, MSH2, MSH3, MSH6, and EXO1. These mutations only cause weak MMR defects as single mutants but cause strong MMR defects when combined with each other. Most of the mutations obtained caused amino acid substitutions in MLH1 or PMS1, and these clustered in either the ATP-binding region or the MLH1-PMS1 interaction regions of these proteins. The mutations showed two other types of interactions: specific pairs of mutations showed unlinked noncomplementation in diploid strains, and the defect caused by pairs of mutations could be suppressed by high-copy-number expression of a third gene, an effect that showed allele and overexpressed gene specificity. These results support a model in which EXO1 plays a structural role in MMR and stabilizes multiprotein complexes containing a number of MMR proteins. A similar role is proposed for PCNA based on the data presented.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, UCSD School of Medicine-CMME3080, 9500 Gilman Dr., La Jolla, CA 92093-0660. Phone: (858) 534-7804. Fax: (858) 534-7750. E-mail: rkolodner{at}ucsd.edu.

Molecular and Cellular Biology, August 2001, p. 5142-5155, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5142-5155.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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