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Nucleic Acids Research Advance Access published online on June 18, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm432
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© 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

Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation

Lothar Schermelleh1, Andrea Haemmer1, Fabio Spada1, Nicole Rösing1, Daniela Meilinger1, Ulrich Rothbauer1, M. Cristina Cardoso2 and Heinrich Leonhardt1,*

1Ludwig Maximilians University Munich (LMU), Department of Biology II, 82152 Martinsried, Germany and 2Max Delbrück Center for Molecular Medicine (MDC), 13125 Berlin, Germany

*To whom correspondence should be addressed. Tel: +49-89-2180-74232; Fax: +49-89-2180-74236; Email: h.leonhardt{at}lmu.de

Received February 2, 2007. Accepted May 14, 2007.

Postreplicative maintenance of genomic methylation patterns was proposed to depend largely on the binding of DNA methyltransferase 1 (Dnmt1) to PCNA, a core component of the replication machinery. We investigated how the slow and discontinuous DNA methylation could be mechanistically linked with fast and processive DNA replication. Using photobleaching and quantitative live cell imaging we show that Dnmt1 binding to PCNA is highly dynamic. Activity measurements of a PCNA-binding-deficient mutant with an enzyme-trapping assay in living cells showed that this interaction accounts for a 2-fold increase in methylation efficiency. Expression of this mutant in mouse dnmt1–/– embryonic stem (ES) cells restored CpG island methylation. Thus association of Dnmt1 with the replication machinery enhances methylation efficiency, but is not strictly required for maintaining global methylation. The transient nature of this interaction accommodates the different kinetics of DNA replication and methylation while contributing to faithful propagation of epigenetic information.


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