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Nucleic Acids Research Advance Access originally published online on November 5, 2007
Nucleic Acids Research 2008 36(1):67-75; doi:10.1093/nar/gkm943
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Nucleic Acids Research, 2008, Vol. 36, No. 1 67-75
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Mismatch Repair proteins are recruited to replicating DNA through interaction with Proliferating Cell Nuclear Antigen (PCNA)

Prerna Jasmine Masih1, Dimiter Kunnev2 and Thomas Melendy1,2,*

1Department of Cellular and Molecular Biology, Roswell Park Cancer Institute, and 2Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA

*To whom correspondence should be addressed. Tel: +1 716 829 3789; Fax: +1 716 829 3889; Email: tmelendy{at}buffalo.edu

Received July 25, 2007. Revised October 5, 2007. Accepted October 14, 2007.

Mismatch Repair (MMR) is closely linked to DNA replication; however, other than the role of the replicative sliding clamp (PCNA) in various MMR functions, the linkage between DNA replication and MMR has been difficult to investigate. Here we use an in vitro DNA replication system based on simian virus 40, to investigate MMR recruitment to replicating DNA. Both DNA replication and MMR proteins are recruited to replicating DNA in an origin-dependent fashion. Primer synthesis is required for recruitment of both PCNA and MMR proteins, but not for recruitment of the single-stranded DNA-binding protein (RPA). Blocking PCNA recruitment to replicating DNA with a p21-based polypeptide blocks PCNA and MMR, but not RPA recruitment. Once PCNA and subsequent proteins required for replication are loaded onto DNA, addition of p21 leaves PCNA on the replicating DNA, but actively displaces MMR proteins. These findings indicate that the MMR machinery is recruited to replicating DNA through its interaction with PCNA, and suggests that this occurs via binding of the MMR proteins to the multi-protein interaction sites on PCNA. These studies demonstrate the utility of this system for further investigation of the role of DNA replication in MMR.

Present address: Dimiter Kunnev, Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14214, USA.


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