Academic journal article Genetics

Role of Proliferating Cell Nuclear Antigen Interactions in the Mismatch Repair-Dependent Processing of Mitotic and Meiotic Recombination Intermediates in Yeast

Academic journal article Genetics

Role of Proliferating Cell Nuclear Antigen Interactions in the Mismatch Repair-Dependent Processing of Mitotic and Meiotic Recombination Intermediates in Yeast

Article excerpt

ABSTRACT

The mismatch repair (MMR) system is critical not only for the repair of DNA replication errors, but also for the regulation of mitotic and meiotic recombination processes. In a manner analogous to its ability to remove replication errors, the MMR system can remove mismatches in heteroduplex recombination intermediates to generate gene conversion events. Alternatively, such mismatches can trigger an MMR-dependent antirecombination activity that blocks the completion of recombination, thereby limiting interactions between diverged sequences. In Saccharomyces cerevisiae, the MMR proteins Msh3, Msh6, and Mlh1 interact with proliferating cell nuclear antigen (PCNA), and mutations that disrupt these interactions result in a mutator phenotype. In addition, some mutations in the PCNA-encoding POL30 gene increase mutation rates in an MMR-dependent manner. In the current study, pol30, mlh1, and msh6 mutants were used to examine whether MMR-PCNA interactions are similarly important during mitotic and meiotic recombination. We find that MMR-PCNA interactions are important for repairing mismatches formed during meiotic recombination, but play only a relatively minor role in regulating the fidelity of mitotic recombination.

THE failure to accurately replicate and repair genomic DNA leads to a wide variety of somatic and germ-line mutations, most of which are deleterious. Organisms thus have evolved multiple mechanisms to promotethe stabilityofDNAandensure faithfulgenome propagation. One of these mechanisms is the mismatch repair (MMR) system, best known for its role in correcting errors made by DNA polymerases during DNA replication (reviewed by Harfe and Jinks-Robertson 2000; Schofield and Hsieh 2003; Kunkel and Erie 2005). In addition to this replication-associated "spellchecker" function, the MMR system promotes genome stability via an antirecombination activity that prevents recombination between diverged sequences (reviewed by Surtees et al. 2004). Because such sequences are not identical, there is the potential for mismatches to be present within heteroduplex recombination intermediates. The MMR system recognizes such mismatches and prevents recombination from going to completion, thereby limiting detrimental genome rearrangements between dispersed repeated sequences. In some cases, a single mismatch within heteroduplex DNA is sufficient to reduce mitotic recombination in anMMR-dependent manner (Datta et al. 1997).

In addition to the spellchecker and antirecombination functions that promote mitotic genome stability, theMMRsystemis important during meiosis, specifically in meiotic recombination (reviewed by Hoffmann and Borts 2004; Surtees et al. 2004). As inmitosis, sequence divergence can trigger meiotic antirecombination activity of the MMR machinery, an activity thought to be important for enforcing homolog-homolog interactions and species barriers. Mismatches formed in meiotic recombination intermediates between different alleles, however, are more often simply repaired by the MMR system. Depending on which strand is used as the template for repair, either Mendelian segregation of the alleles will be restored or a gene conversion event will occur. In the nomenclature of eight-spored asci, restoration-type repair is manifested as 4:4 events while gene conversion results in 6:2 or 2:6 allele segregation. If MMR fails to correct a mismatch, the resulting meiotic product will have both alleles, resulting in a 5:3 or 3:5 ratio, referred to as postmeiotic segregation (PMS). Loss of MMR function typically results in an increase in PMS events and a concomitant reduction in gene conversion. Finally, in addition to mismatch correction, certain MMR proteins have also been shown to be involved in the processing of meiotic recombination intermediates to produce crossovers (Hunter and Borts 1997;Wang et al. 1999).

The mechanism of MMR associated with DNA replication is best understood in prokaryotes, where it involves the proteins MutS, MutL, and MutH (reviewed by Iyer et al. …

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