Skip Navigation

Nucleic Acids Research 2005 33(17):5703-5712; doi:10.1093/nar/gki878
This Article
Right arrow Full Text Freely available
Right arrow Print PDF (1418K) Freely available
Right arrow Screen PDF (400K) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrow Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Right arrow Articles by Hidaka, M.
Right arrow Articles by Sekiguchi, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hidaka, M.
Right arrow Articles by Sekiguchi, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CarcinogenesisHome page
M. Sanada, M. Hidaka, Y. Takagi, T. Y. Takano, Y. Nakatsu, T. Tsuzuki, and M. Sekiguchi
Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis
Carcinogenesis, December 1, 2007; 28(12): 2657 - 2663.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.