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Nucleic Acids Research 2005 33(16):5073-5081; doi:10.1093/nar/gki829
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Published online 7 September 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Human AP endonuclease suppresses DNA mismatch repair activity leading to microsatellite instability

In-Youb Chang1,2, Soo-Hyun Kim1,3, Hyun-Ju Cho1,3, Do Young Lee1,3, Mi-Hwa Kim1,3, Myung-Hee Chung4 and Ho Jin You1,3,*

1Research Center for Proteinous Materials, Chosun University 375 Seusuk-dong, Gwangju 501-759, Korea 2Department of Anatomy, School of Medicine, Chosun University 375 Seusuk-dong, Gwangju 501-759, Korea 3Department of Pharmacology, School of Medicine, Chosun University 375 Seusuk-dong, Gwangju 501-759, Korea 4Department of Pharmacology, College of medicine, Seoul National University 28, Yongon-dong, Seoul 110-799, Korea

*To whom correspondence should be addressed. Tel: +82 62 230 6337; Fax: +82 62 233 3720; Email: hjyou{at}mail.chosun.ac.kr

Received May 16, 2005. Revised July 25, 2005. Accepted August 24, 2005.

The multifunctional mammalian apurinic/apyrimidinic (AP) endonuclease (APE) participates in the repair of AP sites in the cellular DNA as well as participating in the redox regulation of the transcription factor function. The function of APE is considered as the rate-limiting step in DNA base excision repair. Paradoxically, an unbalanced increase in APE protein leads to genetic instability. Therefore, we investigated the mechanisms of genetic instability that are induced by APE. Here, we report that the overexpression of APE protein disrupts the repair of DNA mismatches, which results in microsatellite instability (MSI). We found that expression of APE protein led to the suppression of the repair of DNA mismatches in the normal human fibroblast cells. Western blot analysis revealed that hMSH6 protein was markedly reduced in the APE-expressing cells. Moreover, the addition of purified Mut{alpha} (MSH2 and MSH6 complex) to the extracts from the APE-expressing cells led to the restoration of mismatch repair (MMR) activity. By performing MMR activity assay and MSI analysis, we found that the co-expression of hMSH6 and APE exhibited the microsatellite stability, whereas the expression of APE alone generated the MSI-high phenotype. The APE-mediated decrease in MMR activity described here demonstrates the presence of a new and highly effective APE-mediated mechanism for MSI.


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[Abstract] [Full Text] [PDF]


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