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Molecular and Cellular Biology, November 1999, p. 7801-7815, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Saccharomyces cerevisiae pol30 (Proliferating Cell Nuclear Antigen) Mutations Impair Replication Fidelity and Mismatch Repair

Clark Chen,1 Bradley J. Merrill,2,3 Patrick J. Lau,1 Connie Holm,2,3 and Richard D. Kolodner1,3,4,5,*

Ludwig Institute for Cancer Research,1 Department of Pharmacology,2 Division of Cellular and Molecular Medicine,3 Cancer Center,4 and Department of Medicine,5 University of California---San Diego School of Medicine, La Jolla, California 92093

Received 26 May 1999/Returned for modification 2 July 1999/Accepted 30 July 1999

To understand the role of POL30 in mutation suppression, 11 Saccharomyces cerevisiae pol30 mutator mutants were characterized. These mutants were grouped based on their mutagenic defects. Many pol30 mutants harbor multiple mutagenic defects and were placed in more than one group. Group A mutations (pol30-52, -104, -108, and -126) caused defects in mismatch repair (MMR). These mutants exhibited mutation rates and spectra reminiscent of MMR-defective mutants and were defective in an in vivo MMR assay. The mutation rates of group A mutants were enhanced by a msh2 or a msh6 mutation, indicating that MMR deficiency is not the only mutagenic defect present. Group B mutants (pol30-45, -103, -105, -126, and -114) exhibited increased accumulation of either deletions alone or a combination of deletions and duplications (4 to 60 bp). All deletion and duplication breakpoints were flanked by 3 to 7 bp of imperfect direct repeats. Genetic analysis of one representative group B mutant, pol30-126, suggested polymerase slippage as the likely mutagenic mechanism. Group C mutants (pol30-100, -103, -105, -108, and -114) accumulated base substitutions and exhibited synergistic increases in mutation rate when combined with msh6 mutations, suggesting increased DNA polymerase misincorporation as a mutagenic defect. The synthetic lethality between a group A mutant, pol30-104, and rad52 was almost completely suppressed by the inactivation of MSH2. Moreover, pol30-104 caused a hyperrecombination phenotype that was partially suppressed by a msh2 mutation. These results suggest that pol30-104 strains accumulate DNA breaks in a MSH2-dependent manner.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, UCSD School of Medicine-CMME3080, 9500 Gilman Dr., La Jolla, CA 92093-0660. Phone: (619) 534-7804. Fax: (619) 534-7750. E-mail: rkolodner{at}ucsd.edu.

Molecular and Cellular Biology, November 1999, p. 7801-7815, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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