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Nucleic Acids Research 2005 33(17):5703-5712; doi:10.1093/nar/gki878
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Published online 4 October 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

PCNA–MutS{alpha}-mediated binding of MutL{alpha} to replicative DNA with mismatched bases to induce apoptosis in human cells

Masumi Hidaka1,*, Yasumitsu Takagi2, Tomoko Y. Takano1 and Mutsuo Sekiguchi1,2

1Department of Molecular Biology, Biomolecular Engineering Research Institute 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan 2Frontier Research Center, Fukuoka Dental College 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan

*To whom correspondence should be addressed. Tel: +81 6 6872 8216; Fax: +81 6 6872 8210; Email: hidaka{at}beri.or.jp

Received August 11, 2005. Revised September 14, 2005. Accepted September 14, 2005.

Modified bases, such as O6-methylguanines, are produced in cells exposed to alkylating agents and cause apoptosis. In human cells treated with N-methyl-N-nitrosourea, we detected a protein complex composed of MutS{alpha}, MutL{alpha} and PCNA on damaged DNA by immunoprecipitation method using chromatin extracts, in which protein–protein interactions were stabilized by chemical crosslinking. Time course experiments revealed that MutS{alpha}, consisting of MSH2 and MSH6 proteins, and PCNA bind to DNA to form an initial complex, and MutL{alpha}, composed of MLH1 and PMS2, binds to the complex when the DNA is damaged. This sequential mode of binding was further confirmed by the findings that the association of PCNA–MutS{alpha} complex on chromatin was observed even in the cells that lack MLH1, whereas in the absence of MSH2 no association of MutL{alpha} with the chromatin was achieved. Moreover, reduction in the PCNA content by small-interfering RNA or inhibition of DNA replication by aphidicolin, an inhibitor of DNA polymerase, significantly reduced the levels of the PCNA–MutS{alpha}–MutL{alpha} complex and also suppressed an increase in the caspase-3 activity, a hallmark for the induction of apoptosis. These observations imply that the induction of apoptosis is coupled with the progression of DNA replication through the action of PCNA.


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[Abstract] [Full Text] [PDF]


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