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Proc Natl Acad Sci U S A. 2009 May 26;106(21):8495-500. doi: 10.1073/pnas.0903654106. Epub 2009 May 6.

A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair.

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  • 1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

Mismatch repair contributes to genetic stability, and inactivation of the mammalian pathway leads to tumor development. Mismatch correction occurs by an excision-repair mechanism and has been shown to depend on the 5' to 3' hydrolytic activity exonuclease 1 (Exo1) in eukaryotic cells. However, genetic and biochemical studies have indicated that one or more Exo1-independent modes of mismatch repair also exist. We have analyzed repair of nicked circular heteroduplex DNA in extracts of Exo1-deficient mouse embryo fibroblast cells. Exo1-independent repair under these conditions is MutL alpha-dependent and requires functional integrity of the MutL alpha endonuclease metal-binding motif. In contrast to the Exo1-dependent reaction, we have been unable to detect a gapped excision intermediate in Exo1-deficient extracts when repair DNA synthesis is blocked. A possible explanation for this finding has been provided by analysis of a purified system comprised of MutS alpha, MutL alpha, replication factor C, proliferating cell nuclear antigen, replication protein A, and DNA polymerase delta that supports Exo1-independent repair in vitro. Repair in this system depends on MutL alpha incision of the nicked heteroduplex strand and dNTP-dependent synthesis-driven displacement of a DNA segment spanning the mismatch. Such a mechanism may account, at least in part, for the Exo1-independent repair that occurs in eukaryotic cells, and hence the modest cancer predisposition of Exo1-deficient mammalian cells.

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